3-amino-1,5,6,7-tetrahydro-4H-indol-4-ones

ABSTRACT

Compounds of formula (I) as described herein processes for their production and their use as anti-cancer agents.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the national stage of International Application No.PCT/EP2016/063540, filed internationally on Jun. 14, 2016, which claimsthe benefit of European Application No. 15172613.0, filed Jun. 17, 2015,International Application No. PCT/EP2015/063527, filed Jun. 17, 2015,and European Application No. 15177393.4, filed Jul. 17, 2015.

SUBMISSION OF SEQUENCE LISTING ON ASCII TEXT FILE

The content of the following submission on ASCII text file isincorporated herein by reference in its entirety: a computer readableform (CRF) of the Sequence Listing (file name: 777052019100SEQLIST.TXT,date recorded: Dec. 11, 2017, size: 7 KB).

FIELD OF APPLICATION OF THE INVENTION

The invention relates to substituted tetrahydro-4H-indol-4-onecompounds, processes for their production and uses thereof.

BACKGROUND OF THE INVENTION

One of the most fundamental characteristics of cancer cells is theirability to sustain chronic proliferation whereas in normal tissues theentry into and progression through the cell divison cycle is tightlycontrolled to ensure a homeostasis of cell number and maintenance ofnormal tissue function. Loss of proliferation control was emphasized asone of the six hallmarks of cancer [Hanahan D and Weinberg R A, Cell100, 57, 2000; Hanahan D and Weinberg R A, Cell 144, 646, 2011].

The eukaryotic cell division cycle (or cell cycle) ensures theduplication of the genome and its distribution to the daughter cells bypassing through a coordinated and regulated sequence of events. The cellcycle is divided into four successive phases:

1. The G1 phase represents the time before the DNA replication, in whichthe cell grows and is sensitive to external stimuli.

2. In the S phase the cell replicates its DNA, and

3. in the G2 phase preparations are made for entry into mitosis.

4. In mitosis (M phase), the duplicated chromosomes get separatedsupported by a spindle device built from microtubules, and cell divisioninto two daughter cells is completed.

To ensure the extraordinary high fidelity required for an accuratedistribution of the chromosomes to the daughter cells, the passagethrough the cell cycle is strictly regulated and controlled. The enzymesthat are necessary for the progression through the cycle must beactivated at the correct time and are also turned off again as soon asthe corresponding phase is passed. Corresponding control points(“checkpoints”) stop or delay the progression through the cell cycle ifDNA damage is detected, or the DNA replication or the creation of thespindle device is not yet completed. The mitotic checkpoint (also knownas spindle checkpoint or spindle assembly checkpoint) controls theaccurate attachment of microtubules of the spindle device to thekinetochors (the attachment site for microtubules) of the duplicatedchromosomes. The mitotic checkpoint is active as long as unattachedkinetochores are present and generates a wait-signal to give thedividing cell the time to ensure that each kinetochore is attached to aspindle pole, and to correct attachment errors. Thus the mitoticcheckpoint prevents a mitotic cell from completing cell division withunattached or erroneously attached chromosomes [Suijkerbuijk S J andKops G J, Biochem. Biophys. Acta 1786, 24, 2008; Musacchio A and SalmonE D, Nat. Rev. Mol. Cell. Biol. 8, 379, 2007]. Once all kinetochores areattached with the mitotic spindle poles in a correct bipolar(amphitelic) fashion, the checkpoint is satisfied and the cell entersanaphase and proceeds through mitosis.

The mitotic checkpoint is established by a complex network of a numberof essential proteins, including members of the MAD (mitotic arrestdeficient, MAD 1-3) and Bub (Budding uninhibited by benzimidazole, Bub1-3) families, Mpsl kinase, cdc20, as well as other components [reviewedin Bolanos-Garcia V M and Blundell T L, Trends Biochem. Sci. 36, 141,2010], many of these being over-expressed in proliferating cells (e.g.cancer cells) and tissues [Yuan B et al., Clin. Cancer Res. 12, 405,2006]. The major function of an unsatisfied mitotic checkpoint is tokeep the anaphase-promoting complex/cyclosome (APC/C) in an inactivestate. As soon as the checkpoint gets satisfied the APC/Cubiquitin-ligase targets cyclin B and securin for proteolyticdegradation leading to separation of the paired chromosomes and exitfrom mitosis.

Inactive mutations of the Ser/Thr kinase Bub1 prevented the delay inprogression through mitosis upon treatment of cells of the yeast S.cerevisiae with microtubule-destabilizing drugs, which led to theidentification of Bub1 as a mitotic checkpoint protein [Roberts B T etal., Mal. Cell Biol., 14, 8282, 1994]. A number of recent publicationsprovide evidence that Bub1 plays multiple roles during mitosis whichhave been reviewed by Elowe [Elowe S, Mol. Cell. Biol. 31, 3085, 2011].In particular, Bub1 is one of the first mitotic checkpoint proteins thatbinds to the kinetochores of duplicated chromosomes and probably acts asa scaffolding protein to constitute the mitotic checkpoint complex.Furthermore, via phosphorylation of histone H2A, Bub1 localizes theprotein shugoshin to the centromeric region of the chromosomes toprevent premature segregation of the paired chromosomes [Kawashima etal. Science 327, 172, 2010]. In addition, together with a Thr-3phosphorylated Histone H3 the shugoshin protein functions as a bindingsite for the chromosomal passenger complex which includes the proteinssurvivin, borealin, INCENP and Aurora B. The chromosomal passengercomplex is seen as a tension sensor within the mitotic checkpointmechanism, which dissolves erroneously formed microtubule-kinetochorattachments such as syntelic (both sister kinetochors are attached toone spindle pole) or merotelic (one kinetochor is attached to twospindle poles) attachments [Watanabe Y, Cold Spring Harb. Symp. Quant.Biol. 75, 419, 2010]. Recent data suggest that the phosphorylation ofhistone H2A at Thr 121 by Bub1 kinase is sufficient to localize AuroraBkinase to fulfill the attachment error correction checkpoint [Ricke etal. J. Cell Biol. 199, 931-949, 2012].

Incomplete mitotic checkpoint function has been linked with aneuploidyand tumourigenesis [Weaver B A and Cleveland D W, Cancer Res. 67, 10103,2007; King R W, Biochim Biophys Acta 1786, 4, 2008]. In contrast,complete inhibition of the mitotic checkpoint has been recognised toresult in severe chromosome missegregation and induction of apoptosis intumour cells [Kops G J et al., Nature Rev. Cancer 5, 773, 2005; SchmidtM and Medema R H, Cell Cycle 5, 159, 2006; Schmidt M and Bastians H,Drug Res. Updates 10, 162, 2007]. Thus, mitotic checkpoint abrogationthrough pharmacological inhibition of components of the mitoticcheckpoint, such as Bub1 kinase, represents a new approach for thetreatment of proliferative disorders, including solid tumours such ascarcinomas, sarcomas, leukaemias and lymphoid malignancies or otherdisorders, associated with uncontrolled cellular proliferation.

The present invention relates to chemical compounds that inhibit Bub1kinase.

Established anti-mitotic drugs such as vinca alkaloids, taxanes orepothilones activate the mitotic checkpoint, inducing a mitotic arresteither by stabilising or destabilising microtubule dynamics. This arrestprevents separation of the duplicated chromosomes to form the twodaughter cells. Prolonged arrest in mitosis forces a cell either intomitotic exit without cytokinesis (mitotic slippage or adaption) or intomitotic catastrophe leading to cell death [Rieder C L and Maiato H, Dev.Cell 7, 637, 2004]. In contrast, inhibitors of Bub1 prevent theestablishment and/or functionality of the mitotic checkpoint andinterfere with spindle attachment error correction, which finallyresults in severe chromosomal missegregation, induction of apoptosis andcell death.

These findings suggest that Bub1 inhibitors should be of therapeuticvalue for the treatment of proliferative disorders associated withenhanced uncontrolled proliferative cellular processes such as, forexample, cancer, inflammation, arthritis, viral diseases, cardiovasculardiseases, or fungal diseases in a warm-blooded animal such as man.

WO 2013/050438, WO 2013/092512, WO 2013/167698, WO 2014/147203, WO2014/147204, WO2014202590, WO2014202588, WO2014202584, WO2014202583WO2015/063003, disclose substituted indazoles, substituted pyrazoles,and substituted cycloalkylpyrazoles, which are Bub1 kinase inhibitors.

WO2015/193339 discloses 3-Amino-1,5,6,7-tetrahydro-4H-indol-4-ones whichare Bub1 kinase inhibitors.

Due to the fact that especially cancer disease as being expressed byuncontrolled proliferative cellular processes in tissues of differentorgans of the human- or animal body still is not considered to be acontrolled disease in that sufficient drug therapies already exist,there is a strong need to provide further new therapeutically usefuldrugs, preferably inhibiting new targets and providing new therapeuticoptions (e.g. drugs with improved pharmacological properties).

DESCRIPTION OF THE INVENTION

Therefore, inhibitors of Bub1 represent valuable compounds that shouldcomplement therapeutic options either as single agents or in combinationwith other drugs.

In accordance with a first aspect, the invention relates to a compoundof formula (I),

in which:

-   -   R¹ represents hydrogen or C₁-C₆-alkyl;    -   R² represents hydroxy, C₂-C₄-alkenyl, R⁷R⁸N—, R¹⁰—O—C(O)—,        R⁷R⁸N—C(O)—, R⁶—C(O)—NR⁹—, or R¹¹—(C₁-C₄-alkyl)-;        -   wherein said C₂-C₄-alkenyl is optionally substituted with            halogen, R¹⁰—O—C(O)—, R⁷R⁸N— or phenyl, wherein said phenyl            group is optionally substituted, one or more times,            independently from each other, with R⁴,    -   R³ represents hydrogen or C₁-C₆-alkyl;    -   A represents a group selected from:

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule and said group is optionally            substituted, one or more times, independently from each            other, with R⁴;

    -   R⁴ represents halogen, hydroxy, nitro, cyano, C₁-C₄-alkyl,        C₁-C₄-alkoxy, C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy,        C₁-C₄-hydroxyalkyl, C₁-C₄-alkyl-C(O)—, R¹⁰—O—C(O)—, R⁷R⁸N—C(O)—,        C₁-C₄-alkyl-C(O)—NH—, R⁷R⁸N—, or R⁷R⁸N—SO₂—;

    -   E represents a group

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule;

    -   R⁵ represents, independently from each other, halogen, hydroxy,        nitro, cyano, R⁹R¹⁰N—, (R¹³—C(O)—)(R¹⁴—C(O)—)N—, C₁-C₄-alkyl,        C₃-C₆-cycloalkyl, C₁-C₆-alkoxy, C₁-C₄-haloalkyl,        C₁-C₆-haloalkoxy, R⁶—C(O)—NR⁹— or R⁷R⁸N—C(O)—NR⁹—,        -   wherein said C₁-C₄-alkoxy is optionally substituted, one or            more times, independently from each other, with a            substituent selected from hydroxy, C₁-C₄-alkoxy,            C₃-C₆-cycloalkyl, and 4- to 6-membered heterocycloalkyl,

    -   Q represents O or N—OH;

    -   R⁶ represents, independently from each other, C₁-C₆-alkyl,        C₃-C₆-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or        heteroaryl,        -   wherein said C₁-C₆-alkyl is optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, nitro, cyano, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,            C₃-C₆-cycloalkyl, R⁷R⁸N— or phenyl optionally substituted,            one or more times, independently from each other, with R⁴,        -   wherein said C₃-C₆-cycloalkyl, 4- to 6-membered            heterocycloalkyl, phenyl or heteroaryl groups are optionally            substituted, one or more times, independently from each            other, with halogen, hydroxy, nitro, cyano, C₁-C₆-alkyl,            C₁-C₄-alkoxy, C₁-C₄-haloalkyl, R¹⁰—O—C(O)— or            C₁-C₄-haloalkoxy;

    -   R⁷, R⁸ represent, independently from each other, hydrogen,        C₁-C₆-alkyl, C₃-C₆-cycloalkyl, R¹⁰—O—C(O)— or phenyl,        -   wherein said C₁-C₆-alkyl is optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₃-C₆-cycloalkyl            optionally substituted one time with hydroxy, 4- to            6-membered heterocycloalkyl, heteroaryl, or R⁹R¹⁰N—,        -   wherein said phenyl group is optionally substituted, one or            more times, independently from each other, with R⁴;        -   or,

    -   R⁷ and R⁸ together with the nitrogen atom to which they are        attached form a 4- to 7-membered nitrogen containing        heterocyclic ring, optionally containing one additional        heteroatom selected from O, NR⁹ and S, and which may be        optionally substituted, one or more times, independently from        each other, with R¹²;        -   whereby when two R¹² substituents are attached to the same            ring carbon atom, together with the carbon atom to which            they are attached, can be linked to one another in such a            way that they jointly form a cyclobutane, azetidine, or            oxetane group;        -   said azetidine being optionally substituted one time with            C₁-C₃-alkyl,

    -   or,

    -   R⁷ and R⁸ together with the nitrogen atom to which they are        attached form a group selected from:

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule,

    -   R⁹ represents hydrogen, or C₁-C₆-alkyl;

    -   R¹⁰ represents hydrogen, C₁-C₆-alkyl or C₃-C₆-cycloalkyl;

    -   R¹¹ represents hydroxy, nitro, cyano, C₃-C₆-cycloalkyl, 4- to        6-membered heterocycloalkyl, C₁-C₄-alkyl-C(O)—, R¹⁰—O—C(O)—,        R⁷R⁹N—C(O)—, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, R⁷R⁸N—, N₃—,        R⁶—C(O)—NR⁹—, R⁶—O—C(O)—NR⁹—, R⁷R⁸N—C(O)—NR⁹—, R⁶—SO₂—NR⁹—,        R⁶—S—, R⁶—SO—, R⁶—SO₂—, R⁷R⁸N—SO₂—;        -   wherein said C₃-C₆-cycloalkyl or 4- to 6-membered            heterocycloalkyl groups are optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, cyano, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyl            or C₁-C₄-haloalkoxy,        -   wherein said C₁-C₄-alkoxy is optionally substituted with            phenyl, wherein said phenyl group is optionally substituted,            one or more times, independently from each other, with R⁴,

    -   R¹² represents halogen, hydroxy, C₁-C₄-alkoxy, C₁-C₄-haloalkyl,        C₁-C₄-haloalkoxy, or R⁹R¹⁰N—;

    -   R¹³, R¹⁴ represent, independently from each other, C₁-C₄-alkyl,        or C₃-C₆-cycloalkyl,        -   wherein said C₃-C₆-cycloalkyl is optionally substituted, one            or more times, independently from each other, with halogen;

    -   m represents 0, 1 or 2;

or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, ora salt of said N-oxide, tautomer or stereoisomer.

In a second aspect, the invention relates to compounds of formula (I) asdescribed supra,

wherein:

-   -   R¹ represents hydrogen or C₁-C₄-alkyl;    -   R² represents hydroxy, C₂-C₄-alkenyl, R⁷R⁸N—, R¹⁰—O—C(O)—,        R⁷R⁸N—C(O)—, R⁶—C(O)—NR⁹—, or R¹¹—(C₁-C₄-alkyl)-;        -   wherein said C₂-C₄-alkenyl is optionally substituted with            halogen, R¹⁰—O—C(O)—, R⁷R⁸N— or phenyl, wherein said phenyl            group is optionally substituted, one or more times,            independently from each other, with R⁴.    -   R³ represents hydrogen or C₁-C₄-alkyl;    -   A represents a group selected from:

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule and said group is optionally            substituted, one or more times, independently from each            other, with R⁴;

    -   R⁴ represents halogen, hydroxy, nitro, cyano, C₁-C₄-alkoxy,        C₁-C₄-haloalkyl, or C₁-C₄-haloalkoxy;

    -   E represents a group

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule;

    -   R⁵ represents, independently from each other, halogen, hydroxy,        cyano, R⁹R¹⁰N—, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyl,        C₁-C₄-haloalkoxy, R⁶—C(O)—NR⁹— or R⁷R⁸N—C(O)—NR⁹—,        -   wherein said C₁-C₄-alkoxy is optionally substituted, one or            more times, independently from each other, with a            substituent selected from hydroxy, C₁-C₄-alkoxy, and            C₃-C₆-cycloalkyl;

    -   Q represents O or N—OH;

    -   R⁶ represents, independently from each other, C₁-C₆-alkyl,        C₃-C₆-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or        heteroaryl,        -   wherein said C₁-C₆-alkyl is optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, cyano, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,            C₃-C₆-cycloalkyl, R⁷R⁸N— or phenyl optionally substituted,            one or more times, independently from each other, with R⁴,        -   wherein said C₃-C₆-cycloalkyl, 4- to 6-membered            heterocycloalkyl, phenyl or heteroaryl groups are optionally            substituted, one or more times, independently from each            other, with halogen, hydroxy, cyano, C₁-C₄-alkyl,            C₁-C₄-alkoxy, C₁-C₄-haloalkyl, R¹⁰—O—C(O)— or            C₁-C₄-haloalkoxy;

    -   R⁷, R⁸ represent, independently from each other, hydrogen,        C₁-C₆-alkyl, C₃-C₆-cycloalkyl, R¹⁰—O—C(O)— or phenyl,        -   wherein said C₁-C₆-alkyl is optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₃-C₆-cycloalkyl            optionally substituted one time with hydroxy, 4- to            6-membered heterocycloalkyl, heteroaryl, or R⁹R¹⁰N—,        -   wherein said phenyl group is optionally substituted, one or            more times, independently from each other, with R⁴;

    -   R⁷ and R⁸ together with the nitrogen atom to which they are        attached form a 4- to 7-membered nitrogen containing        heterocyclic ring, optionally containing one additional        heteroatom selected from O, NR⁹ and S, and which may be        optionally substituted, one or more times, independently from        each other, with R¹²;

    -   R⁹ represents hydrogen or C₁-C₄-alkyl;

    -   R¹⁰ represents hydrogen, C₁-C₄-alkyl, or C₃-C₄-cycloalkyl;

    -   R¹¹ represents hydroxy, cyano, C₃-C₆-cycloalkyl, 4- to        6-membered heterocycloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,        R⁷R⁸N—, N₃—, R⁶—C(O)—NR⁹—, R⁶—O—C(O)—NR⁹—, R⁷R⁸N—C(O)—NR⁹—,        R⁶—SO₂—R⁹—, R⁶—S—, or R⁶—SO—, R⁶—SO₂—;        -   wherein said C₃-C₆-cycloalkyl or 4- to 6-membered            heterocycloalkyl groups are optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, cyano, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyl            or C₁-C₄-haloalkoxy,        -   wherein said C₁-C₄-alkoxy is optionally substituted with            phenyl, wherein said phenyl group is optionally substituted,            one or more times, independently from each other, with R⁴,

    -   R¹² represents halogen, hydroxy, C₁-C₄-alkyl, C₁-C₄-alkoxy,        C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy, or R⁹R¹⁰N—;

    -   m represents 0, 1 or 2;

or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, ora salt of said N-oxide, tautomer or stereoisomer.

In a third aspect, the invention relates to compounds of formula (I) asdescribed supra, wherein:

-   -   R¹ represents hydrogen or C₁-C₂-alkyl;    -   R² represents hydroxy, C₂-C₄-alkenyl, R⁷R⁸N—, R¹⁰—O—C(O)—,        R⁷R⁸N—C(O)—, R⁶—C(O)—NR⁹—, or R¹¹—(C₁-C₄-alkyl)-;        -   wherein said C₂-C₄-alkenyl is optionally substituted with            R¹⁰—O—C(O)—, R⁷R⁸N— or phenyl, wherein said phenyl group is            optionally substituted, one or more times, independently            from each other, with R⁴,    -   R³ represents hydrogen or C₁-C₄-alkyl;    -   A represents a group selected from:

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule and said group is optionally            substituted, one or more times, independently from each            other, with R⁴;

    -   R⁴ represents halogen;

    -   E represents a group

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule;

    -   R⁵ represents, independently from each other, halogen, R⁹R¹⁰N—,        C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, R⁶—C(O)—NR⁹— or R⁷R⁸N—C(O)—NR⁹—,        -   wherein said C₁-C₄-alkoxy is optionally substituted, one or            more times, independently from each other, with a            substituent selected from hydroxy, C₁-C₄-alkoxy, and            C₃-C₄-cycloalkyl;

    -   Q represents O;

    -   R⁶ represents, independently from each other, C₁-C₆-alkyl,        C₃-C₆-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or        heteroaryl,        -   wherein said C₁-C₆-alkyl is optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, C₁-C₂-alkoxy, C₃-C₄-cycloalkyl, R⁷R⁸N— or phenyl            optionally substituted, one or more times, independently            from each other, with R⁴,        -   wherein said C₃-C₆-cycloalkyl, 4- to 6-membered            heterocycloalkyl, phenyl or heteroaryl groups are optionally            substituted, one or more times, independently from each            other, with halogen, hydroxy, C₁-C₄-alkyl,            tert-butyl-O—C(O)—, or C₁-C₄-alkoxy;

    -   R⁷, R⁸ represent, independently from each other, hydrogen,        C₁-C₆-alkyl, C₃-C₄-cycloalkyl, tert-butyl-O—C(O)— or phenyl,        -   wherein said C₁-C₆-alkyl is optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, C₁-C₄-alkoxy, C₃-C₆-cycloalkyl optionally            substituted one time with hydroxy, 4- to 6-membered            heterocycloalkyl, heteroaryl, or R⁹R¹⁰N—,        -   wherein said phenyl group is optionally substituted, one or            more times, independently from each other, with R⁴;

    -   R⁷ and R⁸ together with the nitrogen atom to which they are        attached form a 4- to 6-membered nitrogen containing        heterocyclic ring, optionally containing one additional        heteroatom selected from O and NR⁹, and which may be optionally        substituted, one or more times, independently from each other,        with R¹²;

    -   R⁹ represents hydrogen or C₁-C₂-alkyl;

    -   R¹⁰ represents hydrogen or C₁-C₄-alkyl;

    -   R¹¹ represents hydroxy, 6-membered heterocycloalkyl,        C₁-C₂-alkoxy, R⁷R⁸N—, N₃—, R⁶—C(O)—NR⁹—, R⁶—O—C(O)—NR⁹—,        R⁷R⁸N—C(O)—NR⁹—, R⁶—SO₂—NR⁹—, R⁶—S—, R⁶—SO—, R⁶—SO₂—;        -   wherein said 6-membered heterocycloalkyl group is optionally            substituted, one or more times, independently from each            other, with halogen, hydroxy, cyano, C₁-C₄-alkoxy,            C₁-C₄-haloalkyl or C₁-C₄-haloalkoxy,        -   wherein said C₁-C₄-alkoxy is optionally substituted with            phenyl, wherein said phenyl group is optionally substituted,            one or more times, independently from each other, with R⁴,

    -   R¹² represents halogen, hydroxy, C₁-C₂-alkyl, R⁹R¹⁰N—;

    -   m represents 0, or 1;

or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, ora salt of said N-oxide, tautomer or stereoisomer.

In a fourth aspect, the invention relates to compounds of formula (I) asdescribed supra,

wherein:

-   -   R¹ represents hydrogen or methyl;    -   R² represents hydroxy, C₂-C₄-alkenyl, R⁷R⁸N—, R¹⁰—O—C(O)—,        R⁷R⁸N—C(O)—, R⁶—C(O)—NR⁹—, or R¹¹—(C₁-C₄-alkyl)-;        -   wherein said C₂-C₄-alkenyl is optionally substituted with            HO—C(O)—, (CH₃)₂N— or phenyl, wherein said phenyl group is            optionally substituted one, two or three times with F,    -   R³ represents hydrogen, methyl or ethyl;    -   A represents a group selected from:

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule and said group is optionally            substituted, one or two times, independently from each            other, with R⁴;

    -   R⁴ represents fluoro or chloro;

    -   E represents a group

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule;

    -   R⁵ represents, independently from each other, fluoro, R⁹R¹⁰N—,        C₁-C₂-alkoxy, difluoroethoxy, R⁶—C(O)—NR⁹— or R⁷R⁸N—C(O)—NR⁹—,        -   wherein said C₁-C₂-alkoxy is optionally substituted, one or            two times, independently from each other, with a substituent            selected from hydroxy, methoxy, and cyclopropyl;

Q represents O;

-   -   R⁶ represents, independently from each other, C₁-C₅-alkyl,        C₃-C₄-cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl or        5- to 6-membered heteroaryl,        -   wherein said C₁-C₅-alkyl is optionally substituted, one, two            or three times, independently from each other, with fluoro,            hydroxy, methoxy, cyclopropyl, or R⁷R⁸N— and optionally            substituted one time with phenyl optionally substituted,            one, two or three times, independently from each other, with            R⁴,        -   wherein said C₃-C₄-cycloalkyl, 5- to 6-membered            heterocycloalkyl, phenyl or heteroaryl groups are optionally            substituted, one, two or three times, independently from            each other, with fluoro, chloro, hydroxy, methyl,            tert-butyl-O—C(O)—, methoxy;    -   R⁷, R⁸ represent, independently from each other, hydrogen,        C₁-C₅-alkyl, cyclopropyl, cyclobutyl, tert-butyl-O—C(O)— or        phenyl,        -   wherein said C₁-C₅-alkyl is optionally substituted, one or            more times, independently from each other, with fluoro,            hydroxy, methoxy, C₃-C₄-cycloalkyl optionally substituted            one time with hydroxy, 5-membered heterocycloalkyl,            5-membered heteroaryl, or R⁹R¹⁰N—,        -   wherein said phenyl group is optionally substituted, one, or            two times, independently from each other, with fluoro or            chloro;    -   R⁷ and R⁸ together with the nitrogen atom to which they are        attached form a 4- to 6-membered nitrogen containing        heterocyclic ring, optionally containing one additional        heteroatom selected from O and NR⁹, and which may be optionally        substituted, one or two times, independently from each other,        with R¹²;    -   R⁹ represents hydrogen or methyl;    -   R¹⁰ represents hydrogen, methyl or tert-butyl;    -   R¹¹ represents hydroxy, morpholino, methoxy, R⁷R⁸N—, N₃—,        R⁶—C(O)—NR⁹—, R⁶—O—C(O)—NR⁹—, R⁷R⁸N—C(O)—NR⁹—, R⁶—SO₂—NR⁹—,        R⁶—S—, R⁶—SO—, or R⁸—SO₂—;        -   wherein said methoxy group is optionally substituted with            phenyl;    -   R¹² represents fluoro, hydroxy, methyl, or R⁹R¹⁰N—;    -   m represents 0, or 1;

or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, ora salt of said N-oxide, tautomer or stereoisomer.

In another aspect, the invention relates to compounds of formula (I) asdescribed supra,

wherein:

-   -   R¹ represents hydrogen or C₁-C₄-alkyl;    -   R² represents hydroxy, C₂-C₄-alkenyl, R⁷R⁸N—, R¹⁰—O—C(O)—,        R⁷R⁸N—C(O)—, R⁶—C(O)—NR⁹—, or R¹¹—(CH₂)_(n)—;        -   wherein said C₂-C₄-alkenyl is optionally substituted with            halogen, R¹⁰—O—C(O)—, R⁷R⁸N— or phenyl, wherein said phenyl            group is optionally substituted, one or more times,            independently from each other, with R⁴,    -   R³ represents hydrogen or C₁-C₄-alkyl;    -   A represents a group selected from:

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule and said group is optionally            substituted, one or more times, independently from each            other, with R⁴;

    -   R⁴ represents halogen, hydroxy, nitro, cyano, C₁-C₄-alkoxy,        C₁-C₄-haloalkyl, or C₁-C₄-haloalkoxy;

    -   E represents a group

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule;

    -   R⁵ represents, independently from each other, halogen, hydroxy,        cyano, R⁹R¹⁰N—, C₁-C₁-C₄-alkoxy, C₁-C₄-haloalkyl,        C₁-C₄-haloalkoxy, R⁶—C(O)—NR⁹— or R⁷R⁸N—C(O)—NR⁹—,        -   wherein said C₁-C₄-alkoxy is optionally substituted, one or            more times, independently from each other, with a            substituent selected from hydroxy, C₁-C₄-alkoxy, and            C₃-C₆-cycloalkyl;

    -   Q represents O or N—OH;

    -   R⁶ represents, independently from each other, C₁-C₆-alkyl,        C₃-C₆-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or        heteroaryl,        -   wherein said C₁-C₆-alkyl is optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, cyano, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,            C₃-C₆-cycloalkyl, R⁷R⁸N— or phenyl optionally substituted,            one or more times, independently from each other, with R⁴,        -   wherein said C₃-C₆-cycloalkyl, 4- to 6-membered            heterocycloalkyl, phenyl or heteroaryl groups are optionally            substituted, one or more times, independently from each            other, with halogen, hydroxy, cyano, C₁-C₄-alkoxy,            C₁-C₄-haloalkyl, R¹⁰—O—C(O)— or C₁-C₄-haloalkoxy;

    -   R⁷, R⁸ represent, independently from each other, hydrogen,        C₁-C₆-alkyl, C₃-C₆-cycloalkyl, R¹⁰—O—C(O)— or phenyl,        -   wherein said C₁-C₆-alkyl is optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₃-C₆-cycloalkyl            optionally substituted one time with hydroxy, 4- to            6-membered heterocycloalkyl, heteroaryl, or R⁹R¹⁰N—,        -   wherein said phenyl group is optionally substituted, one or            more times, independently from each other, with R⁴;

    -   R⁷ and R⁸ together with the nitrogen atom to which they are        attached form a 4- to 7-membered nitrogen containing        heterocyclic ring, optionally containing one additional        heteroatom selected from O, NR⁹ and S, and which may be        optionally substituted, one or more times, independently from        each other, with R¹²;

    -   R⁹ represents hydrogen or C₁-C₄-alkyl;

    -   R¹⁰ represents hydrogen, C₁-C₄-alkyl, or C₃-C₄-cycloalkyl;

    -   R¹¹ represents hydroxy, cyano, C₃-C₆-cycloalkyl, 4- to        6-membered heterocycloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,        R⁷R⁸N—, N₃—, R⁶—C(O)—NR⁹—, R⁶—O—C(O)—NR⁹—, R⁷R⁸N—C(O)—NR⁹—,        R⁶—SO₂—NR⁹—, R⁶—S—, or R⁶—SO—, R⁶—SO₂—;        -   wherein said C₃-C₆-cycloalkyl or 4- to 6-membered            heterocycloalkyl groups are optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, cyano, C₁-C₄-alkoxy, C₁-C₄-haloalkyl or            C₁-C₄-haloalkoxy,        -   wherein said C₁-C₄-alkoxy is optionally substituted with            phenyl, wherein said phenyl group is optionally substituted,            one or more times, independently from each other, with R⁴,

    -   R¹² represents halogen, hydroxy, C₁-C₄-alkyl, C₁-C₄-alkoxy,        C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy, or R⁹R¹⁰N—;

    -   m represents 0, 1 or 2;

    -   n represents 1, 2, 3 or 4;

or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, ora salt of said N-oxide, tautomer or stereoisomer.

In another aspect, the invention relates to compounds of formula (I) asdescribed supra,

wherein:

-   -   R¹ represents hydrogen or C₁-C₂-alkyl;    -   R² represents hydroxy, C₂-C₄-alkenyl, R⁷R⁸N—, R¹⁰—O—C(O)—,        R⁷R⁸N—C(O)—, R⁶—C(O)—NR⁹—, or R¹¹—(CH₂)_(n)—;        -   wherein said C₂-C₄-alkenyl is optionally substituted with            R¹⁰—O—C(O)—, R⁷R⁸N— or phenyl, wherein said phenyl group is            optionally substituted, one or more times, independently            from each other, with R⁴,    -   R³ represents hydrogen or C₁-C₄-alkyl;    -   A represents a group selected from:

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule and said group is optionally            substituted, one or more times, independently from each            other, with R⁴;

    -   R⁴ represents halogen;

    -   E represents a group

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule;

    -   R⁵ represents, independently from each other, halogen, R⁹R¹⁰N—,        C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, R⁶—C(O)—NR⁹— or R⁷R⁸N—C(O)—NR⁹—,        -   wherein said C₁-C₄-alkoxy is optionally substituted, one or            more times, independently from each other, with a            substituent selected from hydroxy, C₁-C₄-alkoxy, and            C₃-C₄-cycloalkyl;

    -   Q represents O;

    -   R⁶ represents, independently from each other, C₁-C₆-alkyl,        C₃-C₆-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or        heteroaryl,        -   wherein said C₁-C₆-alkyl is optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, C₁-C₂-alkoxy, C₃-C₄-cycloalkyl, R⁷R⁸N— or phenyl            optionally substituted, one or more times, independently            from each other, with R⁴,        -   wherein said C₃-C₆-cycloalkyl, 4- to 6-membered            heterocycloalkyl, phenyl or heteroaryl groups are optionally            substituted, one or more times, independently from each            other, with halogen, hydroxy, C₁-C₄-alkyl,            tert-butyl-O—C(O)—, or C₁-C₄-alkoxy;

    -   R⁷, R⁸ represent, independently from each other, hydrogen,        C₁-C₆-alkyl, C₃-C₄-cycloalkyl, tert-butyl-O—C(O)— or phenyl,        -   wherein said C₁-C₆-alkyl is optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, C₁-C₄-alkoxy, C₃-C₆-cycloalkyl optionally            substituted one time with hydroxy, 4- to 6-membered            heterocycloalkyl, heteroaryl, or R⁹R¹⁰N—,        -   wherein said phenyl group is optionally substituted, one or            more times, independently from each other, with R⁴;

    -   R⁷ and R⁸ together with the nitrogen atom to which they are        attached form a 4- to 6-membered nitrogen containing        heterocyclic ring, optionally containing one additional        heteroatom selected from O and NR⁹, and which may be optionally        substituted, one or more times, independently from each other,        with R¹²;

    -   R⁹ represents hydrogen or C₁-C₂-alkyl;

    -   R¹⁰ represents hydrogen or C₁-C₂-alkyl;

    -   R¹¹ represents hydroxy, 6-membered heterocycloalkyl,        C₁-C₂-alkoxy, R⁷R⁸N—, N₃—, R⁶—C(O)—NR⁹—, R⁶—O—C(O)—NR⁹—,        R⁷R⁸N—C(O)—NR⁹—, R⁶—SO₂—NR⁹—, R⁶—S—, R⁶—SO—, R⁶—SO₂—;        -   wherein said 6-membered heterocycloalkyl group is optionally            substituted, one or more times, independently from each            other, with halogen, hydroxy, cyano, C₁-C₄-alkoxy,            C₁-C₄-haloalkyl or C₁-C₄-haloalkoxy,        -   wherein said C₁-C₄-alkoxy is optionally substituted with            phenyl, wherein said phenyl group is optionally substituted,            one or more times, independently from each other, with R⁴,

    -   R¹² represents halogen, hydroxy, C₁-C₂-alkyl, R⁹R¹⁰N—;

    -   m represents O, or 1;

    -   n represents 1, 2, 3 or 4;

or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, ora salt of said N-oxide, tautomer or stereoisomer.

In another aspect, the invention relates to compounds of formula (I) asdescribed supra,

wherein:

-   -   R¹ represents hydrogen or methyl;    -   R² represents hydroxy, C₂-C₄-alkenyl, R⁷R⁸N—, R¹⁰—O—C(O)—,        R⁷R⁸N—C(O)—, R⁶—C(O)—NR⁹—, or R¹¹—(CH₂)_(n)—;        -   wherein said C₂-C₄-alkenyl is optionally substituted with            HO—C(O)—, (CH₃)₂N— or phenyl, wherein said phenyl group is            optionally substituted one, two or three times with F,    -   R³ represents hydrogen, methyl or ethyl;    -   A represents a group selected from:

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule;

    -   R⁴ represents fluoro or chloro;

    -   E represents a group

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule;

    -   R⁵ represents, independently from each other, fluoro, R⁹R¹⁰N—,        C₁-C₂-alkoxy, difluoroethoxy, R⁶—C(O)—NR⁹— or R⁷R⁸N—C(O)—NR⁹—,        -   wherein said C₁-C₂-alkoxy is optionally substituted, one or            two times, independently from each other, with a substituent            selected from hydroxy, methoxy, and cyclopropyl;

Q represents O;

-   -   R⁶ represents, independently from each other, C₁-C₅-alkyl,        C₃-C₄-cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl or        5- to 6-membered heteroaryl,        -   wherein said C₁-C₅-alkyl is optionally substituted, one, two            or three times, independently from each other, with fluoro,            hydroxy, methoxy, cyclopropyl, or R⁷R⁸N— and optionally            substituted one time with phenyl optionally substituted,            one, two or three times, independently from each other, with            R⁴,        -   wherein said C₃-C₄-cycloalkyl, 5- to 6-membered            heterocycloalkyl, phenyl or heteroaryl groups are optionally            substituted, one, two or three times, independently from            each other, with fluoro, chloro, hydroxy, methyl,            tert-butyl-O—C(O)—, methoxy;    -   R⁷, R⁸ represent, independently from each other, hydrogen,        C₁-C₅-alkyl, cyclopropyl, tert-butyl-O—C(O)— or phenyl,        -   wherein said C₁-C₅-alkyl is optionally substituted, one or            more times, independently from each other, with fluoro,            hydroxy, methoxy, C₃-C₄-cycloalkyl optionally substituted            one time with hydroxy, 5-membered heterocycloalkyl,            5-membered heteroaryl, or R⁹R¹⁰N—,        -   wherein said phenyl group is optionally substituted, one, or            two times, independently from each other, with fluoro or            chloro;    -   R⁷ and R⁸ together with the nitrogen atom to which they are        attached form a 4- to 6-membered nitrogen containing        heterocyclic ring, optionally containing one additional        heteroatom selected from O and NR⁹, and which may be optionally        substituted, one or two times, independently from each other,        with R¹²;    -   R⁹ represents hydrogen or methyl;    -   R¹⁰ represents hydrogen or methyl;    -   R¹¹ represents hydroxy, morpholino, methoxy, R⁷R⁸N—, N₃—,        R⁶—C(O)—NR⁹—, R⁶—O—C(O)—NR⁹—, R⁷R⁸N—C(O)—NR⁹—, R⁶—SO₂—NR⁹—,        R⁶—S—, or R⁸—SO₂—;        -   wherein said methoxy group is optionally substituted with            phenyl;    -   R¹² represents fluoro, hydroxy, methyl, or R⁹R¹⁰N—;    -   m represents 1, or 1;    -   n represents 1 or 4;

or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, ora salt of said N-oxide, tautomer or stereoisomer.

In another aspect, the invention relates to compounds of formula (I) asdescribed supra,

wherein:

-   -   R¹ represents hydrogen or C₁-C₂-alkyl;    -   R² represents hydroxy, C₂-C₄-alkenyl, R⁷R⁸N—, R¹⁰—O—C(O)—,        R⁷R⁸N—C(O)—, R⁶—C(O)—NR⁹—, or R¹¹—(C₁-C₄-alkyl)-;        -   wherein said C₂-C₄-alkenyl is optionally substituted with            R¹⁰—O—C(O)—, R⁷R⁸N— or phenyl, wherein said phenyl group is            optionally substituted, one or more times, independently            from each other, with R⁴,    -   R³ represents hydrogen or C₁-C₄-alkyl;    -   A represents a group selected from:

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule and said group is optionally            substituted, one or more times, independently from each            other, with R⁴;

    -   R⁴ represents halogen;

    -   E represents a group

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule;

    -   R⁵ represents, independently from each other, halogen, R⁹R¹⁰N—,        C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, R^(6a)—C(O)—NR⁹—, or        R⁷R⁸N—C(O)—NR⁹—,        -   wherein said C₁-C₄-alkoxy is optionally substituted, one or            more times, independently from each other, with a            substituent selected from hydroxy, C₁-C₄-alkoxy, and            C₃-C₄-cycloalkyl;

    -   Q represents O;

    -   R⁶ represents, independently from each other, C₁-C₆-alkyl,        C₃-C₆-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or        heteroaryl,        -   wherein said C₁-C₆-alkyl is optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, C₁-C₂-alkoxy, C₃-C₄-cycloalkyl, R⁷R⁸N— or phenyl            optionally substituted, one or more times, independently            from each other, with R⁴,        -   wherein said C₃-C₆-cycloalkyl, 4- to 6-membered            heterocycloalkyl, phenyl or heteroaryl groups are optionally            substituted, one or more times, independently from each            other, with halogen, hydroxy, tert-butyl-O—C(O)—, or            C₁-C₄-alkoxy;

    -   R^(6a) represents, independently from each other, C₁-C₂-alkyl,        C₃-C₆-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or        heteroaryl,        -   wherein said C₁-C₂-alkyl is optionally substituted one time            with halogen, hydroxy, C₁-C₂-alkoxy, C₃-C₄-cycloalkyl,            R⁷R⁸N— or phenyl optionally substituted, one or more times,            independently from each other, with R⁴,        -   wherein said C₃-C₆-cycloalkyl, 4- to 6-membered            heterocycloalkyl, phenyl or heteroaryl groups are optionally            substituted, one or more times, independently from each            other, with halogen, hydroxy, C₁-C₄-alkyl,            tert-butyl-O—C(O)—, or C₁-C₄-alkoxy;

    -   R⁷, R⁸ represent, independently from each other, hydrogen,        C₁-C₃-alkyl, C₃-C₄-cycloalkyl, tert-butyl-O—C(O)— or phenyl,        -   wherein said C₁-C₆-alkyl is optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, C₁-C₂-alkoxy, C₃-C₆-cycloalkyl optionally            substituted one time with hydroxy, 4- to 6-membered            heterocycloalkyl, heteroaryl, or R⁹R¹⁰N—,        -   wherein said phenyl group is optionally substituted, one or            more times, independently from each other, with R⁴;

    -   R⁷ and R⁸ together with the nitrogen atom to which they are        attached form a 4- to 6-membered nitrogen containing        heterocyclic ring, optionally containing one additional        heteroatom selected from O and NR⁹, and which may be optionally        substituted, one or more times, independently from each other,        with R¹²;

    -   R^(7a), R^(8a) represent, independently from each other,        hydrogen, C₁-C₄-alkyl, or C₃-C₄-cycloalkyl,        -   wherein said C₁-C₄-alkyl is optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, C₁-C₄-alkoxy, C₃-C₆-cycloalkyl optionally            substituted one time with hydroxy, 4- to 6-membered            heterocycloalkyl, heteroaryl, or R⁹R¹⁰N—,

    -   R⁹ represents hydrogen or C₁-C₂-alkyl;

    -   R¹⁰ represents hydrogen or C₁-C₄-alkyl;

    -   R¹¹ represents hydroxy, 6-membered heterocycloalkyl,        C₁-C₂-alkoxy, R⁷R⁸N—, N₃—, R⁶—C(O)—NR⁹—, R⁶—O—C(O)—NR⁹—,        R^(7a)R^(8a)N—C(O)—NR⁹—, R⁶—SO₂—NR⁹—, R⁶—S—, R⁶—SO—, R⁶—SO₂—;        -   wherein said 6-membered heterocycloalkyl group is optionally            substituted, one or more times, independently from each            other, with halogen, hydroxy, cyano, C₁-C₄-alkyl,            C₁-C₄-alkoxy, C₁-C₄-haloalkyl or C₁-C₄-haloalkoxy,        -   wherein said C₁-C₄-alkoxy is optionally substituted with            phenyl, wherein said phenyl group is optionally substituted,            one or more times, independently from each other, with R⁴,

    -   R¹² represents halogen, hydroxy, R⁹R¹⁰N—;

    -   m represents 0, or 1;

or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, ora salt of said N-oxide, tautomer or stereoisomer.

In another aspect, the invention relates to compounds of formula (I) asdescribed supra, wherein:

-   -   R¹ represents hydrogen;    -   R² represents hydroxy, C₂-C₄-alkenyl, R⁷R⁸N—, R¹⁰—O—C(O)—,        R⁷R⁸N—C(O)—, R⁶—C(O)—NR⁹—, or R¹¹—(C₁-C₄-alkyl)-;        -   wherein said C₂-C₄-alkenyl is optionally substituted with            R¹⁰—O—C(O)—, R⁷R³N— or phenyl, wherein said phenyl group is            optionally substituted, one or more times, independently            from each other, with R⁴,    -   R³ represents hydrogen or C₁-C₄-alkyl;    -   A represents a group selected from:

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule and said group is optionally            substituted, one or more times, independently from each            other, with R⁴;

    -   R⁴ represents halogen;

    -   E represents a group

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule;

    -   R⁵ represents, independently from each other, halogen, R⁹R¹⁰N—,        C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, R^(6a)—C(O)—NR⁹—, or        R⁷R⁶N—C(O)—NR⁹—,        -   wherein said C₁-C₄-alkoxy is optionally substituted, one or            more times, independently from each other, with a            substituent selected from hydroxy, C₁-C₄-alkoxy, and            C₃-C₄-cycloalkyl;        -   Q represents O;

    -   R⁶ represents, independently from each other, C₁-C₆-alkyl,        C₃-C₆-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or        heteroaryl,        -   wherein said C₁-C₆-alkyl is optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, C₁-C₂-alkoxy, C₃-C₄-cycloalkyl, R⁷R⁹N— or phenyl            optionally substituted, one or more times, independently            from each other, with R⁴,        -   wherein said C₃-C₆-cycloalkyl, 4- to 6-membered            heterocycloalkyl, phenyl or heteroaryl groups are optionally            substituted, one or more times, independently from each            other, with halogen, hydroxy, C₁-C₄-alkyl,            tert-butyl-O—C(O)—, or C₁-C₄-alkoxy;

    -   R^(6a) represents, independently from each other, C₁-C₂-alkyl,        C₃-C₆-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or        heteroaryl,        -   wherein said C₁-C₂-alkyl is optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, C₁-C₂-alkoxy, C₃-C₄-cycloalkyl, R⁷R⁸N— or phenyl            optionally substituted, one or more times, independently            from each other, with R⁴,        -   wherein said C₃-C₆-cycloalkyl, 4- to 6-membered            heterocycloalkyl, phenyl or heteroaryl groups are optionally            substituted, one or more times, independently from each            other, with halogen, hydroxy, C₁-C₄-alkyl,            tert-butyl-O—C(O)—, or C₁-C₄-alkoxy;

    -   R⁷, R⁸ represent, independently from each other, hydrogen,        C₁-C₃-alkyl, C₃-C₄-cycloalkyl, tert-butyl-O—C(O)— or phenyl,        -   wherein said C₁-C₆-alkyl is optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, C₁-C₂-alkoxy, C₃-C₆-cycloalkyl optionally            substituted one time with hydroxy, 4- to 6-membered            heterocycloalkyl, heteroaryl, or R⁹R¹⁰N—,        -   wherein said phenyl group is optionally substituted, one or            more times, independently from each other, with R⁴;

    -   R⁷ and R⁸ together with the nitrogen atom to which they are        attached form a 4- to 6-membered nitrogen containing        heterocyclic ring, optionally containing one additional        heteroatom selected from O and NR⁹, and which may be optionally        substituted, one or more times, independently from each other,        with R¹²;

    -   R^(7a)R^(8a) represent, independently from each other, hydrogen,        C₁-C₄-alkyl, or C₃-C₄-cycloalkyl,

    -   wherein said C₁-C₄-alkyl is optionally substituted, one or more        times, independently from each other, with halogen, hydroxy,        C₁-C₄-alkoxy, C₃-C₆-cycloalkyl optionally substituted one time        with hydroxy, 4- to 6-membered heterocycloalkyl, heteroaryl, or        R⁹R¹⁰N—,

    -   R⁹ represents hydrogen or C₁-C₂-alkyl;

    -   R¹⁰ represents hydrogen or C₁-C₄-alkyl;

    -   R¹¹ represents hydroxy, 6-membered heterocycloalkyl,        C₁-C₂-alkoxy, R⁷R⁹N—, N₃—, R⁶—C(O)—NR⁹—, R⁶—O—C(O)—NR⁹—,        R^(7a)R^(8a)N—C(O)—NR⁹—, R⁶—SO₂—NR⁹—, R⁶—S—, R⁶—SO—, R⁶—SO₂—;        -   wherein said 6-membered heterocycloalkyl group is optionally            substituted, one or more times, independently from each            other, with halogen, hydroxy, cyano, C₁-C₄-alkyl,            C₁-C₄-alkoxy, C₁-C₄-haloalkyl or C₁-C₄-haloalkoxy,        -   wherein said C₁-C₄-alkoxy is optionally substituted with            phenyl, wherein said phenyl group is optionally substituted,            one or more times, independently from each other, with R⁴,

    -   R¹² represents halogen, hydroxy, R⁹R¹⁰N—;

    -   m represents 0, or 1;

or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, ora salt of said N-oxide, tautomer or stereoisomer.

In accordance with another aspect, the invention relates to a compoundof formula (I), which is selected from the group consisting of:

(6RS)-6-(hydroxymethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,

or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, ora salt of said N-oxide, tautomer or stereoisomer.

In accordance with another aspect, the invention relates to a compoundof formula (I), which is selected from the group consisting of:

-   tert-butyl    [(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamate,-   (6RS)-6-[(benzyloxy)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   tert-butyl    [(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]carbamate,-   (6RS)-6-amino-3-anilino-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one    hydrochloride,-   N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]cyclopropanecarboxamide,-   (6RS)-4-oxo-N-phenyl-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   methyl    (6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate,-   4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic    acid,-   (6RS)—N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-4-oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-(2-hydroxyethyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   methyl    (6RS)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate,-   methyl    (6RS)-2-(3-methoxypyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate,-   (6RS)—N-(2-methoxyethyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-ethyl-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-6-(morpholin-4-ylcarbonyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-3-(phenylamino)-2-(pyridin-4-yl)-6-(pyrrolidin-1-ylcarbonyl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-6-(azetidin-1-ylcarbonyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)—N-(cyclopropylmethyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-(cyclopropylmethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-methyl-4-oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N,N-dimethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide-   (6RS)—N-ethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-tert-butyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-3-(phenylamino)-6-(piperidin-1-ylcarbonyl)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-4-oxo-3-(phenylamino)-N-(propan-2-yl)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-6-(hydroxymethyl)-6-methyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   methyl    (6RS)-2-(2-aminopyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate,-   (6RS)-6-(azidomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-6-[(dimethylamino)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-6-(hydroxymethyl)-1-methyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-6-[tert-butyl(dimethyl)silyl]oxy-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-1-ethyl-6-(hydroxymethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-1-[2-(dimethylamino)ethyl]-6-(hydroxymethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-6-hydroxy-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-6-ethenyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   1-ethyl-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylurea,-   1-cyclopropyl-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylurea,-   1-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-3-propan-2-ylurea,-   1-(furan-2-ylmethyl)-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylurea,-   1-(3-chloro-4-fluorophenyl)-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylurea,-   methyl    [(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamate,-   N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylacetamide,-   N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonamide,-   (6RS)-2-(3-methoxypyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic    acid,-   methyl    (6RS)-2-[2-(acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate,-   (4E)-5-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]pent-4-enoic    acid,-   (4Z)-5-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]pent-4-enoic    acid,-   (6RS)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic    acid,-   (6RS)-6-[(E)-2-(4-fluorophenyl)ethenyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-6-[(Z)-2-(4-fluorophenyl)ethenyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-6-(morpholin-4-ylmethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-6-[methyl(propan-2-yl)amino]methyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-6-[(1E)-3-(dimethylamino)prop-1-en-1-yl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-6-[(1Z)-3-(dimethylamino)prop-1-en-1-yl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   1-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-3-(2RS)-(tetrahydrofuran-2-ylmethyl)urea,-   (6RS)—N-methyl-4-oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6R)—N-methyl-4-oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N,N-dimethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6R)—N,N-dimethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6S)—N,N-dimethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6S)—N-methyl-4-oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-6-[(ethylsulfanyl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   4-fluoro-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylbenzenesulfonamide,-   2-methoxyethyl    [(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamate,-   2-fluoroethyl    [(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamate,-   (6RS)-6-[(1,3-benzothiazol-2-ylsulfanyl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-2-[2-(acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic    acid,-   N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcyclopropanecarboxamide,-   2-methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylpropanamide,-   2-methoxy-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylacetamide,-   N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcyclobutanecarboxamide,-   N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylpropane-2-sulfonamide,-   (6RS)—N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6R)—N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6S)—N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-2-(3-fluoropyridin-4-yl)-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-2-(3-methoxypyridin-4-yl)-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-2-(3-fluoropyridin-4-yl)-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-(2-hydroxyethyl)-2-(3-methoxypyridin-4-yl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-6-[(ethylsulfonyl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   3-methoxy-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylpropanamide,-   (6RS)-2-[2-(acetylamino)pyridin-4-yl]-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-2-[2-(acetylamino)pyridin-4-yl]-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   methyl    (6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate,-   methyl    (6R)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate,-   methyl    (6S)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate,-   (6RS)-2-(2-aminopyridin-4-yl)-6-(hydroxymethyl)-3-(phenylamino)-1,5,6,7-tetrahydro-4H-indol-4-one,-   4-fluoro-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylbenzamide,-   tert-butyl    [(2S)-1-oxo-1-([(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylamino)propan-2-yl]carbamate,-   tert-butyl    (2S)-2-([(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamoyl)pyrrolidine-1-carboxylate,-   (2S)-2-hydroxy-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylpropanamide,-   N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-1,3-thiazole-2-carboxamide,-   1-methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-1H-pyrrole-2-carboxamide,-   N-4-[(6RS)-6-(hydroxymethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide,-   N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyltetrahydro-2H-pyran-4-carboxamide,-   N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylfuran-2-carboxamide,-   (6RS)—N-(2-hydroxy-2-methylpropyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-[(2S)-2-hydroxypropyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-(1-hydroxy-2-methylpropan-2-yl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-(2,2-dimethylpropyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-(2-methylpropyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-methyl-N-(2-methylpropyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-[2-(dimethylamino)ethyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-[2-(dimethylamino)ethyl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-methyl-N-[2-(methylamino)ethyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-(2,2-difluoroethyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-N-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-N-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-(2,2-difluoroethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-tert-butyl-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-[(1-hydroxycyclopropyl)methyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-(2-hydroxy-2-methylpropyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-N-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-N-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-[(2R)-2-hydroxypropyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic    acid,-   (6R)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic    acid,-   (6S)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic    acid,-   (6RS)-6-[(4-methylpiperazin-1-yl)carbonyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-6-[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-6-[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-6-[(3-hydroxyazetidin-1-yl)carbonyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)—N,N-diethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]acetamide,-   2-methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]propanamide,-   3-methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide,-   3-hydroxy-3-methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide,-   2-cyclopropyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]acetamide,-   (3S)-3-hydroxy-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide,-   3-hydroxy-2,2-dimethyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]propanamide,-   (6RS)—N-[(2S)-1-hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6R)—N-[(2S)-1-hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6S)—N-[(2S)-1-hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-[(2R)-1-hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6R)—N-[(2R)-1-hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (3R)-3-hydroxy-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide,-   (6S)—N-[(2R)-1-hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-[2-(methylamino)ethyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-L-prolinamide,-   tert-butyl    methyl(3-oxo-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]aminopropyl)carbamate,-   methyl    (6RS)-2-[2-([rel-(1R,2R)-2-fluorocyclopropyl]carbonylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate,-   (6RS)-6-[(1,3-benzothiazol-2-ylsulfonyl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-2-[2-([(1R,2R)-2-fluorocyclopropyl]carbonylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic    acid,-   (6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic    acid,-   methyl    (6RS)-2-2-[(4-fluorobenzoyl)amino]pyridin-4-yl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate,-   methyl    (6RS)-4-oxo-3-(phenylamino)-2-2-[(1,3-thiazol-5-ylcarbonyl)amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indol-6-carboxylate,-   3,3-dimethyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide,-   (6RS)-2-2-[(4-fluorobenzoyl)amino]pyridin-4-yl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic    acid,-   (6RS)-4-oxo-3-(phenylamino)-2-2-[(1,3-thiazol-5-ylcarbonyl)amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indol-6-carboxylic    acid,-   N³-methyl-N-[(6RS)-4-oxo-3-(phelamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]beta-alaninamide    trifluoroacetate,-   (6RS)—N-[(1-hydroxycyclobutyl)methyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (4E)-5-[(6RS)-2-[2-(acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-yl]pent-4-enoic    acid,-   methyl    (6RS)-2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate,-   N-4-[(6RS)-6-(azidomethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide,-   (6RS)—N-(2-methoxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-2-[2-([rel-(1R,2R)-2-fluorocyclopropyl]carbonylamino)pyridin-4-yl]-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-2-[2-([rel-(1R,2R)-2-fluorocyclopropyl]carbonylamino)pyridin-4-yl]-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-(2,2-dimethylpropyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   N-4-[(6RS)-6-(aminomethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide,-   Methyl    (6RS)-3-anilino-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate,-   (6RS)-3-Anilino-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic    acid,-   (6RS)-2-[3-(Cyclopropylmethoxy)pyridin-4-yl]-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   Methyl    (6RS)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate,-   (6RS)-3-Anilino-2-[3-(2-methoxyethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic    acid,-   (6RS)-2-[3-(2-Methoxyethoxy)pyridin-4-yl]-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-(2-Hydroxyethyl)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   Methyl    (6RS)-3-anilino-2-[3-(2-hydroxyethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate,-   (6RS)-2-[3-(2-Hydroxyethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic    acid,-   (6RS)-2-[3-(2,2-Difluoroethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic    acid-   (6RS)—N-Ethyl-N-(2-hydroxyethyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-(2-Hydroxyethyl)-4-oxo-3-(phenylamino)-N-(propan-2-yl)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-[(1-Hydroxycyclobutyl)methyl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-[(2R)-1-Hydroxypropan-2-yl]N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-[(2S)-1-Hydroxypropan-2-yl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   N-(4-{(6RS)-3-Anilino-6-methyl-6-[(4-methylpiperazin-1-yl)carbonyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)acetamide,-   (6RS)-2-(2-Acetamidopyridin-4-yl)-3-anilino-N,N,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   N-{4-[(6RS)-3-Anilino-6-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]carbonyl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide,-   N-(4-{(6RS)-3-Anilino-6-[(3-fluoroazetidin-1-yl)carbonyl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)acetamide,-   N-(4-{(6RS)-3-Anilino-6-[(3,3-difluoroazetidin-1-yl)carbonyl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)acetamide,-   (6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-(2-methoxyethyl)-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N,N-diethyl-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   N-4-[(6RS)-6-Methyl-6-(2-oxa-6-azaspiro[3.3]hept-6-ylcarbonyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide,-   (6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-[(2S)-2-methoxypropyl]-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-[(2S)-1-methoxypropan-2-yl]-N,    6-d    imethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-(2-methoxy-2-methylpropyl)-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N,6-dimethyl-4-oxo-3-(phenylamino)-N-propyl-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-(2,2-d    imethylpropyl)-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   N-4-[(6RS)-6-[(3R)-3-(Dimethylamino)pyrrolidin-1-yl]carbonyl-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide,-   N-4-[(6RS)-6-Methyl-6-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide,-   (6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N,6-dimethyl-N-(2-methylpropyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   N-4-[(6RS)-6-Methyl-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylcarbonyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide,-   N-4-[(6RS)-6-[(Ethylsulfanyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide,-   N-(4-(6RS)-Oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)acetamide,-   N-4-[(6RS)-6-[(tert-Butylsulfanyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide,-   (6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(S)-propan-2-ylsulfinyl]methyl-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-2-2-[(4-Fluorobenzoyl)amino]pyridin-4-yl-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-2-2-[(4-Fluorobenzoyl)amino]pyridin-4-yl-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N,N-Dimethyl-4-oxo-3-(phenylamino)-2-2-[(1,3-thiazol-5-ylcarbonyl)amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-(2-Hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-2-[(1,3-thiazol-5-ylcarbonyl)amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   N-{4-[(6RS)-3-Anilino-6-{[(methylsulfonyl)amino]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide,-   N-{4-[(6RS)-6-(Acetamidomethyl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide,-   N-{[(6RS)-2-(2-Acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl}-4′-methoxybiphenyl-4-carboxamide,-   5-[(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-yl]pentanoic    acid,-   (6RS)-3-Anilino-N,N-diisopropyl-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-3-Anilino-2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-N,N-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-3-Anilino-2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-N-(2-hydroxyethyl)-N-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-3-Anilino-2-[3-(2-hydroxyethoxy)pyridin-4-yl]-N,N-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-3-Anilino-2-[3-(2-hydroxyethoxy)pyridin-4-yl]-N-(2-hydroxyethyl)-N-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-3-Anilino-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-N,N-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   Methyl    (6RS)-3-anilino-2-[2-({[(1RS)-2,2-difluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate,-   (6RS)-3-Anilino-2-[2-({[(1RS)-2,2-difluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic    acid,-   (6RS)-3-Anilino-2-[2-({[(1RS)-2,2-difluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N,N-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   N-(4-{(6RS)-3-Anilino-6-[(isopropylsulfanyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-2-yl}pyridin-2-yl)-4-fluoro-3-methoxybenzamide,-   N-(4-{(6RS)-3-Anilino-6-[(isopropylsulfanyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-2-yl}pyridin-2-yl)-2-fluoro-2-methylpropanamide,-   1-(4-{(6RS)-3-Anilino-6-[(isopropylsulfanyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-2-yl}pyridin-2-yl)-3-cyclopropylurea,-   1-(4-{(6RS)-3-Anilino-6-[(isopropylsulfonyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-2-yl}pyridin-2-yl)-3-cyclopropylurea,-   N-{[(6RS)-3-Anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl}-L-alaninamide,-   (6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N,N,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-3-Anilino-N,N-diethyl-2-[2-({[(1S,23)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N,6-dimethyl-4-oxo-N-propyl-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N-isobutyl-N,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-3-Anilino-N-(cyclopropylmethyl)-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N,6-dimethyl-4-oxo-N-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (1S,2S)—N-{4-[(6RS)-3-Anilino-6-methyl-4-oxo-6-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}-2-fluorocyclopropanecarboxamide,-   (1S,2S)—N-{4-[(6RS)-3-Anilino-6-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}-2-fluorocyclopropanecarboxamide,-   (1S,2S)—N-{4-[(6RS)-3-Anilino-6-methyl-4-oxo-6-(piperidin-1-ylcarbonyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}-2-fluorocyclopropanecarboxamide,-   N-{4-[(6RS)-3-Anilino-6-({[2-(d    imethylamino)ethyl]sulfanyl}methyl)-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide,-   N-(4-{(6RS)-3-Anilino-6-[(isopropylsulfonyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-2-yl}pyridin-2-yl)-4-fluoro-N-methylbenzamide,-   (6RS)-2-(2-Aminopyridin-4-yl)-6-(hydroxymethyl)-6-methyl-3-(phenylamino)-4,5,6,7-tetrahydro-4H-indol-4-one,-   N-4-[(6RS)-6-[(2-Methoxyethyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide,-   N-4-[(6RS)-6-[(1,3-Oxazol-2-ylsulfanyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide,-   N-(4-(6RS)-4-Oxo-3-(phenylamino)-6-[(1,3-thiazol-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)acetamide,-   N-(4-(6RS)-4-Oxo-3-(phenylamino)-6-[(pyridin-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)acetamide,-   N-4-[(6RS)-6-[(4-Fluorobenzyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide,-   (1S,2S)-2-Fluoro-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)cyclopropanecarboxamide,-   N-(4-(6RS)-4-Oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)-1,3-thiazole-5-carboxamide,-   4-Fluoro-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)benzamide,-   4-Chloro-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)benzamide,-   3,4-Dichloro-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)benzamide-   N-4-[(6RS)-6-[(Ethylsulfonyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide,-   N-(4-(6RS)-4-Oxo-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)acetamide,-   2-Fluoro-2-methyl-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)propanamide,-   4-Fluoro-3-methoxy-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)benzamide,-   N-4-[(6RS)-6-[(tert-Butylsulfonyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide,-   (6RS)-2-2-[(2-Fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,N,6-trimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-2-2-[(2-Fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,6-dimethyl-4-oxo-3-(phenylamino)-N-propyl-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N,N-Diethyl-2-2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-2-2-[(2-Fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,6-dimethyl-N-(2-methylpropyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-2-2-[(2-Fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,6-dimethyl-4-oxo-3-(phenylamino)-N-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-(Cyclopropylmethyl)-2-2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   2-Fluoro-2-methyl-N-4-[(6RS)-6-methyl-4-oxo-3-(phenylamino)-6-(pyrrolid    in-1-ylcarbonyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylpropanamide,-   N-{4-[(6RS)-3-Anilino-6-{[(4-fluorophenyl)sulfanyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide,-   N-(4-{(6RS)-3-Anilino-6-[(isopropylsulfonyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-2-yl}pyridin-2-yl)morpholine-4-carboxamide,-   N-{4-[(6RS)-3-Anilino-6-{[(3,4-dichlorophenyl)sulfanyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide,-   N-{4-[(6RS)-3-Anilino-6-{[(4-chlorophenyl)sulfanyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide,-   N-4-[(6RS)-6-[(4-Fluoro-3-methoxyphenyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide,-   N-4-[(6RS)-6-[(3,4-Difluorophenyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide,-   N-4-[(6RS)-6-[(4-Methoxyphenyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide,-   Methyl    (6RS)-4-oxo-2-(pyridin-4-yl)-3-(pyridin-2-ylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate,-   (6RS)-2-(2-Aminopyridin-4-yl)-3-anilino-6-[(isopropylsulfanyl)methyl]-6-methyl-4,5,6,7-tetrahydro-4H-indol-4-one,-   N-(4-{(6RS)-3-Anilino-4-oxo-6-[(1,3-thiazol-2-ylsulfonyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)acetamide,-   N-{4-[(6RS)-3-Anilino-6-{[(4-fluoro-3-hydroxyphenyl)sulfanyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide,-   N-{4-[(6RS)-3-Anilino-6-{[(2-methoxyethyl)sulfonyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide,-   N-{4-[(6RS)-3-Anilino-6-{[(4-fluorobenzyl)sulfonyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide,-   (6RS)-4-oxo-2-(pyridin-4-yl)-3-(pyridin-2-ylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic    acid,-   tert-butyl    (6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate,-   (6RS)—N,N-dimethyl-4-oxo-2-(pyridin-4-yl)-3-(pyridin-2-ylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-[(2S)-2-hydroxypropyl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-[(2R)-2-hydroxypropyl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-N-[2-(pyrrolidin-1-yl)ethyl]-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-methyl-N-[2-(morpholin-4-yl)ethyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-cyclobutyl-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N—R²S)-1-methoxypropan-2-A-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)—N-(1-methoxy-2-methylpropan-2-yl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   methyl    (6R)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate,-   methyl    (6S)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate,-   (6S)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic    acid,-   (6R)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic    acid,-   (6S)-2-(3-fluoropyridin-4-yl)-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6R)-2-(3-fluoropyridin-4-yl)-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide,-   (6RS)-6-(2-hydroxypropan-2-yl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6R)-6-(2-hydroxypropan-2-yl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6S)-6-(2-hydroxypropan-2-yl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   N-{4-[(6RS)-6-(2-hydroxypropan-2-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide,-   N-{4-[(6RS)-6-(2-hydroxypropan-2-yl)-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide,-   (6RS)-2-(3-fluoropyridin-4-yl)-6-(2-hydroxypropan-2-yl)-3-(phenylamino)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-3-(phenylamino)-6-(prop-2-en-1-yl)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-3-(phenylamino)-6-(prop-2-en-1-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-3-(phenylamino)-6-(prop-2-en-1-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-3-[(3-fluorophenyl)amino]-6-(hydroxymethyl)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-6-({[2-(dimethylamino)ethyl](methyl)amino}methyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-6-{[4-(dimethylamino)piperidin-1-yl]methyl}-3-(phenylamino)-2-(pyridin-4-yl-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)-6-[(4-methylpiperazin-1-yl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one,-   4-fluoro-N-{4-[(6RS)-4-oxo-3-(phenylamino)-6-{[(RS)-propan-2-ylsulfinyl]methyl}-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}benzamide,-   N-{4-[(6RS)-4-oxo-3-(phenylamino)-6-{[(RS)-propan-2-ylsulfinyl]methyl}-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}-1,3-thiazole-5-carboxamide,-   (1S,2S)-2-fluoro-N-{4-[(6RS)-4-oxo-3-(phenylamino)-6-{[(RS)-propan-2-ylsulfinyl]methyl}-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}cyclopropanecarboxamide,-   4-chloro-N-{4-[(6RS)-4-oxo-3-(phenylamino)-6-{[(RS)-propan-2-ylsulfinyl]methyl}-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}benzamide,-   3,4-dichloro-N-{4-[(6RS)-4-oxo-3-(phenylamino)-6-{[(RS)-propan-2-ylsulfinyl]methyl}-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}benzamide,-   (6RS)-6-(aminomethyl)-3-[(3-fluorophenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-indol-4-one,-   (6RS)—N-({3-[(3-fluorophenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl}methyl)acetamide,-   methyl    (6S)-2-(2-aminopyridin-4-yl)-3-[(3-fluorophenyl)amino]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate,-   methyl    (6R)-2-(2-aminopyridin-4-yl)-3-[(3-fluorophenyl)amino]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate,-   (6RS)-2-(2-aminopyridin-4-yl)-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic    acid,-   (6S)-2-(2-aminopyridin-4-yl)-3-[(3-fluorophenyl)amino]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic,-   (6S)-2-(2-aminopyridin-4-yl)-3-[(3-fluorophenyl)amino]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic    acid hydrochloride,-   (6R)-2-(2-aminopyridin-4-yl)-3-[(3-fluorophenyl)amino]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic,-   (6R)-2-(2-aminopyridin-4-yl)-3-[(3-fluorophenyl)amino]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic    acid hydrochloride, and-   (6RS)-3-[(3-fluorophenyl)amino]-6-(hydroxymethyl)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-6-methyl-1,5,6,7-tetrahydro-4H-indol-4-one,

or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, ora salt of said N-oxide, tautomer or stereoisomer.

One special aspect of the invention is intermediate (17),

whereby R¹, R², A, and E have the meaning according to any one of claims1 to 5 or as defined in the aspects and embodiments described herein.

One special aspect of the invention is intermediate (20),

whereby R¹, R², E have the meaning according to any one of claims 1 to 5or as defined in the aspects and embodiments herein.

Another aspect of the invention relates to the use of any of theintermediates described herein for preparing a compound of formula (I)as defined herein or an N-oxide, a salt, a tautomer or a stereoisomer ofsaid compound, or a salt of said N-oxide, tautomer or stereoisomer.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R¹ represents hydrogen or C₁-C₆-alkyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R¹ represents hydrogen or C₁-C₄-alkyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R¹ represents hydrogen or C₁-C₂-alkyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R¹ represents hydrogen or methyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R¹ represents hydrogen.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R² represents hydroxy, C₂-C₄-alkenyl, R⁷R⁸N—, R¹⁰—O—C(O)—,        R⁷R⁸N—C(O)—, R⁶—C(O)—NR⁹—, or R¹¹—(C₁-C₄-alkyl)-;        -   wherein said C₂-C₄-alkenyl is optionally substituted with            halogen, R¹⁰—O—C(O)—, R⁷R⁸N— or phenyl, wherein said phenyl            group is optionally substituted, one or more times,            independently from each other, with R⁴.    -   R² represents hydroxy, C₂-C₄-alkenyl, R⁷R⁸N—, R¹⁰—O—C(O)—,        R⁷R⁸N—C(O)—, R⁶—C(O)—NR⁹—, or R¹¹—(C₁-C₄-alkyl)-;        -   wherein said C₂-C₄-alkenyl is optionally substituted with            halogen, R¹⁰—O—C(O)—, R⁷R⁸N— or phenyl, wherein said phenyl            group is optionally substituted, one or more times,            independently from each other, with R⁴,    -   R² represents hydroxy, C₂-C₄-alkenyl, R⁷R⁸N—, R¹⁰—O—C(O)—,        R⁷R⁸N—C(O)—, R⁶—C(O)—NR⁹—, or R¹¹—(C₁-C₄-alkyl)-;        -   wherein said C₂-C₄-alkenyl is optionally substituted one,            two or three times, independently from each other, with            halogen, and optionally substituted one time with            R¹⁰—O—C(O)—, R⁷R⁸N— or phenyl, wherein said phenyl group is            optionally substituted, one or more times, independently            from each other, with R⁴.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R² represents hydroxy, C₂-C₄-alkenyl, R⁷R⁸N—, R¹⁰—O—C(O)—,        R⁷R⁸N—C(O)—, R⁶—C(O)—NR⁹—, or R¹¹—(CH₂)_(n)—;        -   wherein said C₂-C₄-alkenyl is optionally substituted with            halogen, R¹⁰—O—C(O)—, R⁷R⁸N— or phenyl, wherein said phenyl            group is optionally substituted, one or more times,            independently from each other, with R⁴.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R² represents hydroxy, C₂-C₄-alkenyl, R⁷R⁸N—, R¹⁰—O—C(O)—,        R⁷R⁸N—C(O)—, R⁶—C(O)—NR⁹—, or R¹¹—(CH₂)_(n)—;        -   wherein said C₂-C₄-alkenyl is optionally substituted with            R¹⁰—O—C(O)—, R⁷R⁸N— or phenyl, wherein said phenyl group is            optionally substituted, one or more times, independently            from each other, with R⁴.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R² represents hydroxy, C₂-C₄-alkenyl, R⁷R⁸N—, R¹⁰—O—C(O)—,        R⁷R⁸N—C(O)—, R⁶—C(O)—NR⁹—, or R¹¹—(CH₂)_(n)—;        -   wherein said C₂-C₄-alkenyl is optionally substituted with            HO—C(O)—, (CH₃)₂N— or phenyl, wherein said phenyl group is            optionally substituted one, two or three times with fluoro.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R² represents hydroxy, C₂-C₄-alkenyl, R⁷R⁸N—, R¹⁰—O—C(O)—,        R⁷R⁸N—C(O)—, R⁶—C(O)—NR⁹—, or R¹¹—(C₁-C₄-alkyl)-;        -   wherein said C₂-C₄-alkenyl is optionally substituted with            HO—C(O)—, (CH₃)₂N— or phenyl, wherein said phenyl group is            optionally substituted one, two or three times with F.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R² represents hydroxy, C₂-C₄-alkenyl, R⁷R⁸N—, R¹⁰—O—C(O)—,        R⁷R⁸N—C(O)—, R⁶—C(O)—NR⁹—, or R¹¹—(C₁-C₄-alkyl)-;        -   wherein said C₂-C₄-alkenyl is optionally substituted with            one time with HO—C(O)—, (CH₃)₂N— or phenyl, wherein said            phenyl group is optionally substituted one, two or three            times with F.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R³ represents hydrogen or C₁-C₆-alkyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R³ represents hydrogen or C₁-C₄-alkyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R³ represents hydrogen, methyl or ethyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   A represents a group selected from:

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule and said group is optionally            substituted, one or more times, independently from each            other, with R⁴.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   A represents a group selected from:

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule and said group is optionally            substituted, one or more times, independently from each            other, with R⁴.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   A represents a group selected from:

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   A represents a group selected from:

wherein * indicates the point of attachment of said group with the restof the molecule and said group is optionally substituted, one or twotimes, independently from each other, with R⁴.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

R⁴ represents halogen, hydroxy, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy, C₁-C₄-hydroxyalkyl,C₁-C₄-alkyl-C(O)—, R¹⁰—O—C(O)—, R⁷R⁸N—C(O)—, C₁-C₄-alkyl-C(O)—NH—,R⁷R⁸N—, or R⁷R⁸N—SO₂—.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

R⁴ represents halogen, hydroxy, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkyl, or C₁-C₄-haloalkoxy.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

R⁴ represents halogen.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

R⁴ represents fluoro or chloro.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   E represents a group

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R⁵ represents, independently from each other, halogen, hydroxy,        nitro, cyano, R⁹R¹⁰N—, (R¹³—C(O)—)(R¹⁴—C(O)—)N—, C₁-C₄-alkyl,        C₃-C₆-cycloalkyl, C₁-C₆-alkoxy, C₁-C₄-haloalkyl,        C₁-C₆-haloalkoxy, R⁶—C(O)—NR⁹— or R⁷R⁶N—C(O)—NR⁹—,        -   wherein said C₁-C₄-alkoxy is optionally substituted, one or            more times, independently from each other, with a            substituent selected from hydroxy, C₁-C₄-alkoxy,            C₃-C₆-cycloalkyl, and 4- to 6-membered heterocycloalkyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R⁵ represents, independently from each other, halogen, hydroxy,        nitro, cyano, R⁹R¹⁰N—, (R¹³—C(O)—)(R¹⁴—C(O)—)N—, C₁-C₄-alkyl,        C₃-C₆-cycloalkyl, C₁-C₆-alkoxy, C₁-C₄-haloalkyl,        C₁-C₆-haloalkoxy, R⁶—C(O)—NR⁹— or R⁷R⁸N—C(O)—NR⁹—,        -   wherein said C₁-C₆-alkoxy is optionally substituted, one or            more times, independently from each other, with a            substituent selected from hydroxy, C₁-C₄-alkoxy,            C₃-C₆-cycloalkyl, and 4- to 6-membered heterocycloalkyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R⁵ represents, independently from each other, halogen, hydroxy,        cyano, R⁹R¹⁰N—, C₁-C₄-alkoxy, C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy,        R⁶—C(O)—NR⁹— or R⁷R⁸N—C(O)—NR⁹—,        -   wherein said C₁-C₄-alkoxy is optionally substituted, one or            more times, independently from each other, with a            substituent selected from hydroxy, C₁-C₄-alkoxy, and            C₃-C₆-cycloalkyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R⁵ represents, independently from each other, halogen, R⁹R¹⁰N—,        C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, R⁶—C(O)—NR⁹— or R⁷R⁸N—C(O)—NR⁹—,        -   wherein said C₁-C₄-alkoxy is optionally substituted, one or            more times, independently from each other, with a            substituent selected from hydroxy, C₁-C₄-alkoxy, and            C₃-C₄-cycloalkyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R⁵ represents, independently from each other, fluoro, R⁹R¹⁰N—,        C₁-C₂-alkoxy, difluoroethoxy, R⁶—C(O)—NR⁹— or R⁷R⁸N—C(O)—NR⁹—,        -   wherein said C₁-C₂-alkoxy is optionally substituted, one or            two times, independently from each other, with a substituent            selected from hydroxy, methoxy, and cyclopropyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   Q represents O or N—OH.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   Q represents O.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R⁶ represents, independently from each other, C₁-C₆-alkyl,        C₃-C₆-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or        heteroaryl,        -   wherein said C₁-C₆-alkyl is optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, nitro, cyano, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,            C₃-C₆-cycloalkyl, R⁷R⁸N— or phenyl optionally substituted,            one or more times, independently from each other, with R⁴,        -   wherein said C₃-C₆-cycloalkyl, 4- to 6-membered            heterocycloalkyl, phenyl or heteroaryl groups are optionally            substituted, one or more times, independently from each            other, with halogen, hydroxy, nitro, cyano, C₁-C₆-alkyl,            C₁-C₄-alkoxy, C₁-C₄-haloalkyl, R¹⁰—O—C(O)— or            C₁-C₄-haloalkoxy.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R⁶ represents, independently from each other, C₁-C₆-alkyl,        C₃-C₆-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or        heteroaryl,        -   wherein said C₁-C₆-alkyl is optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, cyano, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,            C₃-C₆-cycloalkyl, R⁷R⁸N— or phenyl optionally substituted,            one or more times, independently from each other, with R⁴,        -   wherein said C₃-C₆-cycloalkyl, 4- to 6-membered            heterocycloalkyl, phenyl or heteroaryl groups are optionally            substituted, one or more times, independently from each            other, with halogen, hydroxy, cyano, C₁-C₄-alkyl,            C₁-C₄-alkoxy, C₁-C₄-haloalkyl, R¹⁰—O—C(O)— or            C₁-C₄-haloalkoxy.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R⁶ represents, independently from each other, C₁-C₆-alkyl,        C₃-C₆-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or        heteroaryl,        -   wherein said C₁-C₆-alkyl is optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, C₁-C₂-alkoxy, C₃-C₄-cycloalkyl, R⁷R⁸N— or phenyl            optionally substituted, one or more times, independently            from each other, with R⁴,        -   wherein said C₃-C₆-cycloalkyl, 4- to 6-membered            heterocycloalkyl, phenyl or heteroaryl groups are optionally            substituted, one or more times, independently from each            other, with halogen, hydroxy, C₁-C₄-alkyl,            tert-butyl-O—C(O)—, or C₁-C₄-alkoxy.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R⁶ represents, independently from each other, C₁-C₆-alkyl,        C₃-C₄-cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl or        5- to 6-membered heteroaryl,        -   wherein said C₁-C₆-alkyl is optionally substituted, one, two            or three times, independently from each other, with fluoro,            hydroxy, methoxy, cyclopropyl, or R⁷R⁸N— and optionally            substituted one time with phenyl optionally substituted,            one, two or three times, independently from each other, with            R⁴,        -   wherein said C₃-C₄-cycloalkyl, 5- to 6-membered            heterocycloalkyl, phenyl or heteroaryl groups are optionally            substituted, one, two or three times, independently from            each other, with fluoro, chloro, hydroxy, methyl,            tert-butyl-O—C(O)—, or methoxy.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R⁷, R⁸ represent, independently from each other, hydrogen,        C₁-C₆-alkyl, C₃-C₆-cycloalkyl, R¹⁰—O—C(O)— or phenyl,        -   wherein said C₁-C₆-alkyl is optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₃-C₆-cycloalkyl            optionally substituted one time with hydroxy, 4- to            6-membered heterocycloalkyl, heteroaryl, or R⁹R¹⁰N—,        -   wherein said phenyl group is optionally substituted, one or            more times, independently from each other, with R⁴.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R⁷ and R⁸ together with the nitrogen atom to which they are        attached form a 4- to 7-membered nitrogen containing        heterocyclic ring, optionally containing one additional        heteroatom selected from O, NR⁹ and S, and which may be        optionally substituted, one or more times, independently from        each other, with R¹²;        -   whereby when two R¹² substituents are attached to the same            ring carbon atom, together with the carbon atom to which            they are attached, can be linked to one another in such a            way that they jointly form a cyclobutane, azetidine, or            oxetane group;        -   said azetidine being optionally substituted one time with            C₁-C₃-alkyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R⁷ and R⁸ together with the nitrogen atom to which they are        attached form a group selected from:

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R⁷, R⁸ represent, independently from each other, hydrogen,        C₁-C₆-alkyl, C₃-C₆-cycloalkyl, R¹⁰—O—C(O)— or phenyl,        -   wherein said C₁-C₆-alkyl is optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₃-C₆-cycloalkyl            optionally substituted one time with hydroxy, 4- to            6-membered heterocycloalkyl, heteroaryl, or R⁹R¹⁰N—,        -   wherein said phenyl group is optionally substituted, one or            more times, independently from each other, with R⁴.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R⁷ and R⁸ together with the nitrogen atom to which they are        attached form a 4- to 7-membered nitrogen containing        heterocyclic ring, optionally containing one additional        heteroatom selected from O, NR⁹ and S, and which may be        optionally substituted, one or more times, independently from        each other, with R¹².

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R⁷, R⁸ represent, independently from each other, hydrogen,        C₁-C₆-alkyl, C₃-C₄-cycloalkyl, tert-butyl-O—C(O)— or phenyl,        -   wherein said C₁-C₆-alkyl is optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, C₁-C₄-alkoxy, C₃-C₆-cycloalkyl optionally            substituted one time with hydroxy, 4- to 6-membered            heterocycloalkyl, heteroaryl, or R⁹R¹⁰N—,

wherein said phenyl group is optionally substituted, one or more times,independently from each other, with R⁴.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R⁷ and R⁸ together with the nitrogen atom to which they are        attached form a 4- to 6-membered nitrogen containing        heterocyclic ring, optionally containing one additional        heteroatom selected from O and NR⁹, and which may be optionally        substituted, one or more times, independently from each other,        with R¹².

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R⁷, R⁸ represent, independently from each other, hydrogen,        C₁-C₅-alkyl, cyclopropyl, tert-butyl-O—C(O)— or phenyl,        -   wherein said C₁-C₅-alkyl is optionally substituted, one or            more times, independently from each other, with fluoro,            hydroxy, methoxy, C₃-C₄-cycloalkyl optionally substituted            one time with hydroxy, 5-membered heterocycloalkyl,            5-membered heteroaryl, or R⁹R¹⁰N—,        -   wherein said phenyl group is optionally substituted, one, or            two times, independently from each other, with fluoro or            chloro.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R⁷, R⁸ represent, independently from each other, hydrogen,        C₁-C₅-alkyl, cyclopropyl, cyclobutyl, tert-butyl-O—C(O)— or        phenyl,        -   wherein said C₁-C₅-alkyl is optionally substituted, one or            more times, independently from each other, with fluoro,            hydroxy, methoxy, C₃-C₄-cycloalkyl optionally substituted            one time with hydroxy, 5-membered heterocycloalkyl,            5-membered heteroaryl, or R⁹R¹⁰N—,        -   wherein said phenyl group is optionally substituted, one, or            two times, independently from each other, with fluoro or            chloro.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R⁷ represents hydrogen, or C₁-C₆-alkyl,    -   R⁸ represents hydrogen, C₁-C₆-alkyl, C₃-C₄-cycloalkyl,        tert-butyl-O—C(O)— or phenyl,        -   wherein said C₁-C₆-alkyl is optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, C₁-C₄-alkoxy, C₃-C₆-cycloalkyl optionally            substituted one time with hydroxy, 4- to 6-membered            heterocycloalkyl, heteroaryl, or R⁹R¹⁰N—,

wherein said phenyl group is optionally substituted, one or more times,independently from each other, with R⁴.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R⁷ represents hydrogen, or C₁-C₅-alkyl,    -   R⁸ represents hydrogen, C₁-C₅-alkyl, cyclopropyl,        tert-butyl-O—C(O)— or phenyl,        -   wherein said C₁-C₅-alkyl is optionally substituted, one or            more times, independently from each other, with fluoro,            hydroxy, methoxy, C₃-C₄-cycloalkyl optionally substituted            one time with hydroxy, 5-membered heterocycloalkyl,            5-membered heteroaryl, or R⁹R¹⁰N—,        -   wherein said phenyl group is optionally substituted, one, or            two times, independently from each other, with fluoro or            chloro.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R⁷ and R⁸ together with the nitrogen atom to which they are        attached form a 4- to 6-membered nitrogen containing        heterocyclic ring, optionally containing one additional        heteroatom selected from O and NR⁹, and which may be optionally        substituted, one or two times, independently from each other,        with R¹².

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R⁹ represents hydrogen,or C₁-C₆-alkyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R⁹ represents hydrogen or C₁-C₄-alkyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R⁹ represents hydrogen or C₁-C₂-alkyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R⁹ represents hydrogen or methyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R¹⁰ represents hydrogen, C₁-C₆-alkyl or C₃-C₆-cycloalkyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R¹⁰ represents hydrogen, C₁-C₄-alkyl, or C₃-C₄-cycloalkyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R¹⁰ represents hydrogen or C₁-C₄-alkyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R¹⁰ represents hydrogen or C₁-C₂-alkyl;

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R¹⁰ represents hydrogen or methyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R¹⁰ represents hydrogen, methyl or tert-butyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R¹¹ represents hydroxy, nitro, cyano, C₃-C₆-cycloalkyl, 4- to        6-membered heterocycloalkyl, C₁-C₄-alkyl-C(O)—, R¹⁰—O—C(O)—,        R⁷R⁸N—C(O)—, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, R⁷R⁸N—, N₃—,        R⁶—C(O)—NR⁹—, R⁶—O—C(O)—NR⁹—, R⁷R⁸N—C(O)—NR⁹—, R⁶—SO₂—NR⁹—,        R⁶—S—, R⁶—SO—, R⁶—SO₂—, R⁷R⁸N—SO₂—;        -   wherein said C₃-C₆-cycloalkyl or 4- to 6-membered            heterocycloalkyl groups are optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, cyano, C₁-C₄-alkoxy, C₁-C₄-haloalkyl or            C₁-C₄-haloalkoxy,        -   wherein said C₁-C₄-alkoxy is optionally substituted with            phenyl, wherein said phenyl group is optionally substituted,            one or more times, independently from each other, with R⁴.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R¹¹ represents hydroxy, cyano, C₃-C₆-cycloalkyl, 4- to        6-membered heterocycloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,        R⁷R⁸N—, N₃—, R⁶—C(O)—NR⁹—, R⁶—O—C(O)—NR⁹—, R⁷R⁸N—C(O)—NR⁹—,        R⁶—SO₂—NR⁹—, R⁶—S—, or R⁶—SO—, R⁶—SO₂—;        -   wherein said C₃-C₆-cycloalkyl or 4- to 6-membered            heterocycloalkyl groups are optionally substituted, one or            more times, independently from each other, with halogen,            hydroxy, cyano, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyl            or C₁-C₄-haloalkoxy,        -   wherein said C₁-C₄-alkoxy is optionally substituted with            phenyl, wherein said phenyl group is optionally substituted,            one or more times, independently from each other, with R⁴.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R¹¹ represents hydroxy, 6-membered heterocycloalkyl,        C₁-C₂-alkoxy, R⁷R⁸N—, N₃—, R⁶—C(O)—NR⁹—, R⁶—O—C(O)—NR⁹—,        R⁷R⁸N—C(O)—NR⁹—, R⁶—SO₂—NR⁹—, R⁶—S—, R⁶—SO—, R⁶—SO₂—;        -   wherein said 6-membered heterocycloalkyl group is optionally            substituted, one or more times, independently from each            other, with halogen, hydroxy, cyano, C₁-C₄-alkoxy,            C₁-C₄-haloalkyl or C₁-C₄-haloalkoxy,        -   wherein said C₁-C₄-alkoxy is optionally substituted with            phenyl, wherein said phenyl group is optionally substituted,            one or more times, independently from each other, with R⁴.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R¹¹ represents hydroxy, morpholino, methoxy, R⁷R⁸N—, N₃—,        R⁶—C(O)—NR⁹—, R⁶—O—C(O)—NR⁹—, R⁷R⁸N—C(O)—NR⁹—, R⁶—SO₂—NR⁹—,        R⁶—S—, or R⁶—SO₂—;        -   wherein said methoxy group is optionally substituted with            phenyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R¹¹ represents hydroxy, morpholino, methoxy, R⁷R⁸N—, N₃—,        R⁶—C(O)—NR⁹—, R⁶—O—C(O)—NR⁹—, R⁷R⁸N—C(O)—NR⁹—, R⁶—SO₂—NR⁹—,        R⁶—S—, R⁶—SO—, or R⁶—SO₂—;        -   wherein said methoxy group is optionally substituted with            phenyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

R¹² represents halogen, hydroxy, C₁-C₄-alkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy, or R⁹R¹⁰N—.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

R¹² represents halogen, hydroxy, C₁-C₄-alkoxy, C₁-C₄-haloalkyl,C₁-C₄-haloalkoxy, or R⁹R¹⁰N—.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

R¹² represents halogen, hydroxy, C₁-C₂-alkyl, R⁹R¹⁰N—.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R¹² represents fluoro, hydroxy, methyl, or R⁹R¹⁰N—.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   R¹³, R¹⁴ represent, independently from each other, C₁-C₄-alkyl,        or C₃-C₆-cycloalkyl,        -   wherein said C₃-C₆-cycloalkyl is optionally substituted, one            or more times, independently from each other, with halogen.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   m represents 0, 1 or 2.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   m represents 0, or 1.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   n represents 1, 2, 3 or 4.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   -   n represents 1 or 4.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I) as described herein, with theproviso that the compound of formula (I) is not

(6RS)-6-(Hydroxymethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

One aspect of the invention are compounds of formula (I) as described inthe examples, as characterized by their names in the title, as claimedin claims 1 to 5, and their structures as well as the subcombinations ofall residues specifically disclosed in the compounds of the examples.

Another aspect of the present invention are the intermediates as usedfor their synthesis.

A further aspect of the invention are compounds according to theinvention, which are present as their salts.

It is to be understood that the present invention relates to anysub-combination within any embodiment or aspect of the present inventionof compounds of formula (I) according to the invention, supra.

More particularly still, the present invention covers compounds offormula (I) according to the invention which are disclosed in theExample section of this text, infra.

In accordance with another aspect, the present invention covers methodsof preparing compounds of formula (I) of the present invention, saidmethods comprising the steps as described in the Experimental Sectionherein.

Another embodiment of the invention are compounds according to theclaims as disclosed in the Claims section wherein the definitions arelimited according to the preferred or more preferred definitions asdisclosed below or specifically disclosed residues of the exemplifiedcompounds and subcombinations thereof.

Definitions

Constituents which are optionally substituted as stated herein, may besubstituted, unless otherwise noted, one or more times, independentlyfrom one another at any possible position. When any variable occurs morethan one time in any constituent, each definition is independent. Forexample, when R¹, R², R³, R⁴, R⁵, R⁶, R^(6a), R⁷, R⁸, R^(7a), R^(8a),R⁹, R¹⁰, R¹¹, R¹², R¹³, and/or R¹⁴, occur more than one time in anycompound of formula (I) each definition of R¹, R², R³, R⁴, R⁵, R⁶,R^(6a), R⁷, R⁸, R^(7a), R^(8a), R⁹, R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ isindependent.

Should a constituent be composed of more than one part, e.g.C₁-C₄-alkoxy-C₁-C₄-alkyl-, the position of a possible substituent can beat any of these parts at any suitable position.

A hyphen at the beginning of the constituent marks the point ofattachment with the rest of the molecule. Should a ring be substitutedthe substitutent could be at any suitable position of the ring, also ona ring nitrogen atom if suitable, unless indicated otherwise.

The term “comprising” when used in the specification includes“consisting of”.

If it is referred to “as mentioned above” or “mentioned above” withinthe description it is referred to any of the disclosures made within thespecification in any of the preceding pages.

“suitable” within the sense of the invention means chemically possibleto be made by methods within the knowledge of a skilled person.

The terms as mentioned in the present text have preferably the followingmeanings:

The term “halogen atom”, “halo-” or “Hal-” is to be understood asmeaning a fluorine, chlorine, bromine or iodine atom, preferably afluorine, chlorine, bromine or iodine atom.

The term “C₁-C₆-alkyl” is to be understood as preferably meaning alinear or branched, saturated, monovalent hydrocarbon group having 1, 2,3, 4, 5 or carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl,hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl,2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl,neo-pentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl,2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl,3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl,2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl group, or anisomer thereof, particularly 1, 2, 3 or 4 carbon atoms (“C₁-C₄-alkyl”),e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl,tert-butyl group, more particularly 1, 2, or 3 carbon atoms(“C₁-C₃-alkyl”) e.g. a methyl, ethyl, n-propyl- or iso-propyl group.

The term “C₂-C₄-alkenyl” is to be understood as meaning a linear orbranched, monovalent hydrocarbon group, which contains one or two doublebonds, and which has 2, 3 or 4 carbon atoms, particularly 2 or 3 carbonatoms (“C₂-C₃-alkenyl”), it being understood that in the case in whichsaid alkenyl group contains more than one double bond, then said doublebonds may be isolated from, or conjugated with, each other. Said alkenylgroup is, for example, a vinyl, allyl, (E)-2-methylvinyl,(Z)-2-methylvinyl, homoallyl, (E)-but-2-enyl, (Z)-but-2-enyl,(E)-but-1-enyl, (Z)-but-1-enyl, iso-propenyl, 2-methylprop-2-enyl,1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl,(Z)-1-methylprop-1-enyl, or buta-1,3-dienyl group. Particularly, saidgroup is vinyl or allyl.

The term “C₁-C₄-haloalkyl” is to be understood as preferably meaning alinear or branched, saturated, monovalent hydrocarbon group in which theterm “C₁-C₄-alkyl” is defined supra, and in which one or more hydrogenatoms is replaced by a halogen atom, in identically or differently, i.e.one halogen atom being independent from another. Particularly, saidhalogen atom is F. Said C₁-C₄-haloalkyl group is, for example, —CF₃,—CHF₂, —CH₂F, —CF₂CF₃, or —CH₂CF₃.

The term “C₁-C₆-alkoxy” is to be understood as preferably meaning alinear or branched, saturated, monovalent, hydrocarbon group offormula-O-alkyl, in which the term “alkyl” is defined supra, e.g. amethoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy,tert-butoxy or sec-butoxy group, or an isomer thereof.

The term “C₁-C₆-haloalkoxy” is to be understood as preferably meaning alinear or branched, saturated, monovalent C₁-C₄-alkoxy group, as definedsupra, in which one or more of the hydrogen atoms is replaced, inidentically or differently, by a halogen atom. Particularly, saidhalogen atom is F. Said C₁-C₆-haloalkoxy group is, for example, —OCF₃,—OCHF₂, —OCH₂F, —OCF₂CF₃, or —OCH₂CF₃.

The term “C₃-C₆-cycloalkyl” is to be understood as meaning a saturated,monovalent, mono-, or bicyclic hydrocarbon ring which contains 3, 4, 5or 6 carbon atoms (“C₃-C₆-cycloalkyl”). Said C₃-C₆-cycloalkyl group isfor example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl, or a bicyclic hydrocarbon ring.

The term “heteroaryl” is understood as meaning a monovalent, monocyclic,aromatic ring system having 5, or 6, ring atoms (a “5- to 6-memberedheteroaryl” group), which contains at least one ring heteroatom atom andoptionally one, two or three further ring heteroatoms from the series N,NR¹⁰, O and/or S, and which is bound via a ring carbon atom or, unlessotherwise defined, optionally via a ring nitrogen atom (when allowed byvalency). R¹⁰ is as defined herein. Optionally, said 5- to 6-memberedheteroaryl can be fused with a benzene ring (benzofused). Preferredheteroaryl benzofused groups include, but are not limited to,1,3-Benzothiazolyl.

Said heteroaryl group can be a 5-membered heteroaryl group, such as, forexample, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as,for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl ortriazinyl. In general, and unless otherwise mentioned, the heteroarylicor heteroarylenic radicals include all the possible isomeric formsthereof, e.g.: tautomers and positional isomers with respect to thepoint of linkage to the rest of the molecule. Thus, for someillustrative non-restricting example, the term pyridinyl includespyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienylincludes thien-2-yl and thien-3-yl.

The term “4- to 7-membered heterocycloalkyl” or “4- to 7-memberedheterocyclic ring”, is to be understood as meaning a saturated orpartially unsaturated, monovalent, mono- or bicyclic hydrocarbon ringwhich contains 3, 4, 5 or 6, carbon atoms, and one or moreheteroatom-containing groups selected from O, S, S(═O), S(═0)₂, andNR¹⁰, in which R¹⁰ is as defined herein; optionally one ring carbon atomis replaced with a C(═O) group, it being possible for saidheterocycloalkyl group to be attached to the rest of the molecule viaany one of the carbon atoms or, if present, the nitrogen atom.

Particularly, said 4- to 7-membered heterocycloalkyl can contain 3, 4,or 5 carbon atoms, and one or more of the above-mentionedheteroatom-containing groups (a “4- to 6-membered heterocycloalkyl”),more particularly said heterocycloalkyl can contain 4 or 5 carbon atoms,and one or more of the above-mentioned heteroatom-containing groups (a“5- to 6-membered heterocycloalkyl”).

Particularly, without being limited thereto, said heterocycloalkyl canbe a 4-membered ring, such as an azetidinyl, oxetanyl, or a 5-memberedring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl,imidazolidinyl, pyrazolidinyl, pyrrolinyl, or a 6-membered ring, such astetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl,piperazinyl, or trithianyl, or a 7-membered ring, such as a diazepanylring, for example. Optionally, said heterocycloalkyl can be benfused.

Said heterocyclyl can be bicyclic, such as, without being limitedthereto, a 5,5-membered ring, e.g. a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring, e.g. ahexahydropyrrolo[1,2-a]pyrazin-2 (1H)-yl ring.

As mentioned supra, said nitrogen atom-containing ring can be partiallyunsaturated, i.e. it can contain one or more double bonds, such as,without being limited thereto, a 2,5-dihydro-1H-pyrrolyl,4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl ring,for example, or, it may be benzo-fused, such as, without being limitedthereto, a dihydroisoquinolinyl ring, for example.

The term “C₁-C₆”, as used throughout this text, e.g. in the context ofthe definition of “C₁-C₆-alkyl” or “C₁-C₆-alkoxy” is to be understood asmeaning an alkyl group having a finite number of carbon atoms of 1 to 6,i.e. 1, 2, 3, 4, 5, or 6 carbon atoms. It is to be understood furtherthat said term “C₁-C₆” is to be interpreted as any sub-range comprisedtherein, e.g. C₁-C₆, C₂-C₅, C₃-C₄, C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅, C₁-C₆,particularly C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅, C₁-C₆ more particularly C₁-C₄;in the case of “C₁-C₆-haloalkyl” or “C₁-C₆-haloalkoxy” even moreparticularly C₁-C₂.

Further, as used herein, the term “C₃-C₆”, as used throughout this text,e.g. in the context of the definition of “C₃-C₆-cycloalkyl”, is to beunderstood as meaning a cycloalkyl group having a finite number ofcarbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to beunderstood further that said term “C₃-C₆” is to be interpreted as anysub-range comprised therein, e.g. C₃-C₆, C₄-C₅, C₃-C₅, C₃-C₄, C₄-C₆,C₅-C₆; particularly C₃-C₆.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

Ring system substituent means a substituent attached to an aromatic ornonaromatic ring system which, for example, replaces an availablehydrogen on the ring system.

As used herein, the term “one or more”, e.g. in the definition of thesubstituents of the compounds of the general formulae of the presentinvention, is understood as meaning “one, two, three, four or five,particularly one, two, three or four, more particularly one, two orthree, even more particularly one or two”.

The invention also includes all suitable isotopic variations of acompound of the invention. An isotopic variation of a compound of theinvention is defined as one in which at least one atom is replaced by anatom having the same atomic number but an atomic mass different from theatomic mass usually or predominantly found in nature. Examples ofisotopes that can be incorporated into a compound of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,sulphur, fluorine, chlorine, bromine and iodine, such as ²H (deuterium),³H (tritium), ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S,³⁶S, ¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁹I and ¹³¹I, respectively. Certainisotopic variations of a compound of the invention, for example, thosein which one or more radioactive isotopes such as ³H or ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionstudies. Tritiated and carbon-14, i.e., ¹⁴C, isotopes are particularlypreferred for their ease of preparation and detectability. Further,substitution with isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements andhence may be preferred in some circumstances. Isotopic variations of acompound of the invention can generally be prepared by conventionalprocedures known by a person skilled in the art such as by theillustrative methods or by the preparations described in the exampleshereafter using appropriate isotopic variations of suitable reagents.

Where the plural form of the word compounds, salts, polymorphs,hydrates, solvates and the like, is used herein, this is taken to meanalso a single compound, salt, polymorph, isomer, hydrate, solvate or thelike.

By “stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The compounds of this invention may contain one or more asymmetriccentre, depending upon the location and nature of the varioussubstituents desired. Asymmetric carbon atoms may be present in the (R)or (S) configuration, resulting in racemic mixtures in the case of asingle asymmetric centre, and diastereomeric mixtures in the case ofmultiple asymmetric centres. In certain instances, asymmetry may also bepresent due to restricted rotation about a given bond, for example, thecentral bond adjoining two substituted aromatic rings of the specifiedcompounds. Substituents on a ring may also be present in either cis ortrans form. It is intended that all such configurations (includingenantiomers and diastereomers), are included within the scope of thepresent invention.

Preferred compounds are those which produce the more desirablebiological activity. Separated, pure or partially purified isomers andstereoisomers or racemic or diastereomeric mixtures of the compounds ofthis invention are also included within the scope of the presentinvention. The purification and the separation of such materials can beaccomplished by standard techniques known in the art.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, for example, by theformation of diastereoisomeric salts using an optically active acid orbase or formation of covalent diastereomers. Examples of appropriateacids are tartaric, diacetyltartaric, ditoluoyltartaric andcamphorsulfonic acid. Mixtures of diastereoisomers can be separated intotheir individual diastereomers on the basis of their physical and/orchemical differences by methods known in the art, for example, bychromatography or fractional crystallisation. The optically active basesor acids are then liberated from the separated diastereomeric salts. Adifferent process for separation of optical isomers involves the use ofchiral chromatography (e.g., chiral HPLC columns), with or withoutconventional derivatisation, optimally chosen to maximise the separationof the enantiomers. Suitable chiral HPLC columns are manufactured byDaicel, e.g., Chiracel OD and Chiracel OJ among many others, allroutinely selectable. Enzymatic separations, with or withoutderivatisation, are also useful. The optically active compounds of thisinvention can likewise be obtained by chiral syntheses utilizingoptically active starting materials.

In order to limit different types of isomers from each other referenceis made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

The present invention includes all possible stereoisomers of thecompounds of the present invention as single stereoisomers, or as anymixture of said stereoisomers, e.g. R- or S-isomers, or E- or Z-isomers,in any ratio. Isolation of a single stereoisomer, e.g. a singleenantiomer or a single diastereomer, of a compound of the presentinvention may be achieved by any suitable state of the art method, suchas chromatography, especially chiral chromatography, for example.

Further, the compounds of the present invention may exist as tautomers.For example, any compound of the present invention which contains apyrazole moiety as a heteroaryl group for example can exist as a 1Htautomer, or a 2H tautomer, or even a mixture in any amount of the twotautomers, or a triazole moiety for example can exist as a 1H tautomer,a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said1H, 2H and 4H tautomers, namely:

The present invention includes all possible tautomers of the compoundsof the present invention as single tautomers, or as any mixture of saidtautomers, in any ratio.

Further, the compounds of the present invention can exist as N-oxides,which are defined in that at least one nitrogen of the compounds of thepresent invention is oxidised. The present invention includes all suchpossible N-oxides.

The present invention also relates to useful forms of the compounds asdisclosed herein, such as metabolites, hydrates, solvates, prodrugs,salts, in particular pharmaceutically acceptable salts, andco-precipitates.

The compounds of the present invention can exist as a hydrate, or as asolvate, wherein the compounds of the present invention contain polarsolvents, in particular water, methanol or ethanol for example asstructural element of the crystal lattice of the compounds. The amountof polar solvents, in particular water, may exist in a stoichiometric ornon-stoichiometric ratio. In the case of stoichiometric solvates, e.g. ahydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc.solvates or hydrates, respectively, are possible. The present inventionincludes all such hydrates or solvates.

Further, the compounds of the present invention can exist in free form,e.g. as a free base, or as a free acid, or as a zwitterion, or can existin the form of a salt. Said salt may be any salt, either an organic orinorganic addition salt, particularly any pharmaceutically acceptableorganic or inorganic addition salt, customarily used in pharmacy.

The term “pharmaceutically acceptable salt” refers to a relativelynon-toxic, inorganic or organic acid addition salt of a compound of thepresent invention. For example, see S. M. Berge, et al. “PharmaceuticalSalts,” J. Pharm. Sci. 1977, 66, 1-19.

A suitable pharmaceutically acceptable salt of the compounds of thepresent invention may be, for example, an acid-addition salt of acompound of the present invention bearing a nitrogen atom, in a chain orin a ring, for example, which is sufficiently basic, such as anacid-addition salt with an inorganic acid, such as hydrochloric,hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric, or nitricacid, for example, or with an organic acid, such as formic, acetic,acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic,heptanoic, undecanoic, lauric, benzoic, salicylic,2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic,cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic,pamoic, pectinic, persulfuric, 3-phenylpropionic, picric, pivalic,2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic,dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluenesulfonic,methansulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic,camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic,malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic,mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic,sulfosalicylic, hemisulfuric, or thiocyanic acid, for example.

Further, another suitably pharmaceutically acceptable salt of a compoundof the present invention which is sufficiently acidic, is an alkalimetal salt, for example a sodium or potassium salt, an alkaline earthmetal salt, for example a calcium or magnesium salt, an ammonium salt ora salt with an organic base which affords a physiologically acceptablecation, for example a salt with N-methyl-glucamine, dimethyl-glucamine,ethyl-glucamine, lysine, dicyclohexylamine, 1,6-hexadiamine,ethanolamine, glucosamine, sarcosine, serinol,tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base,1-amino-2,3,4-butantriol. Additionally, basic nitrogen containing groupsmay be quaternised with such agents as lower alkyl halides such asmethyl, ethyl, propyl, and butyl chlorides, bromides and iodides;dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamylsulfates, long chain halides such as decyl, lauryl, myristyl andstrearyl chlorides, bromides and iodides, aralkyl halides like benzyland phemethyl bromides and others.

Those skilled in the art will further recognise that acid addition saltsof the claimed compounds may be prepared by reaction of the compoundswith the appropriate inorganic or organic acid via any of a number ofknown methods. Alternatively, alkali and alkaline earth metal salts ofacidic compounds of the invention are prepared by reacting the compoundsof the invention with the appropriate base via a variety of knownmethods.

The present invention includes all possible salts of the compounds ofthe present invention as single salts, or as any mixture of said salts,in any ratio.

In the present text, in particular in the Experimental Section, for thesynthesis of intermediates and of examples of the present invention,when a compound is mentioned as a salt form with the corresponding baseor acid, the exact stoichiometric composition of said salt form, asobtained by the respective preparation and/or purification process, is,in most cases, unknown.

Unless specified otherwise, suffixes to chemical names or structuralformulae such as “hydrochloride”, “trifluoroacetate”, “sodium salt”, or“x HCl”, “x CF3COOH”, “x Na+”, for example, are to be understood as nota stoichiometric specification, but solely as a salt form.

This applies analogously to cases in which synthesis intermediates orexample compounds or salts thereof have been obtained, by thepreparation and/or purification processes described, as solvates, suchas hydrates with (if defined) unknown stoichiometric composition.

The salts include water-insoluble and, particularly, water-solublesalts.

Furthermore, derivatives of the compounds according to the invention andthe salts thereof which are converted into a compound according to theinvention or a salt thereof in a biological system (bioprecursors orpro-drugs) are covered by the invention. Said biological system is e.g.a mammalian organism, particularly a human subject. The bioprecursor is,for example, converted into the compound according to the invention or asalt thereof by metabolic processes.

As used herein, the term “in vivo hydrolysable ester” is understood asmeaning an in vivo hydrolysable ester of a compound of the presentinvention containing a carboxy or hydroxy group, for example, apharmaceutically acceptable ester which is hydrolysed in the human oranimal body to produce the parent acid or alcohol. Suitablepharmaceutically acceptable esters for carboxy include for examplealkyl, cycloalkyl and optionally substituted phenylalkyl, in particularbenzyl esters, C₁-C₆ alkoxymethyl esters, e.g. methoxymethyl, C₁-C₆alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters,C₃-C₈ cycloalkoxy-carbonyloxy-C₁-C₆ alkyl esters, e.g.1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, e.g.5-methyl-1,3-dioxolen-2-onylmethyl; and C₁-C₆-alkoxycarbonyloxyethylesters, e.g. 1-methoxycarbonyloxyethyl, and may be formed at any carboxygroup in the compounds of this invention.

An in vivo hydrolysable ester of a compound of the present inventioncontaining a hydroxy group includes inorganic esters such as phosphateesters and [alpha]-acyloxyalkyl ethers and related compounds which as aresult of the in vivo hydrolysis of the ester breakdown to give theparent hydroxy group. Examples of [alpha]-acyloxyalkyl ethers includeacetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of invivo hydrolysable ester forming groups for hydroxy include alkanoyl,benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl,alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl. The present invention covers allsuch esters.

Furthermore, the present invention includes all possible crystallineforms, or polymorphs, of the compounds of the present invention, eitheras single polymorphs, or as a mixture of more than one polymorphs, inany ratio.

In the context of the properties of the compounds of the presentinvention the term “pharmacokinetic profile” means one single parameteror a combination thereof including permeability, bioavailability,exposure, and pharmacodynamic parameters such as duration, or magnitudeof pharmacological effect, as measured in a suitable experiment.Compounds with improved pharmacokinetic profiles can, for example, beused in lower doses to achieve the same effect, may achieve a longerduration of action, or a may achieve a combination of both effects.

The term “combination” in the present invention is used as known topersons skilled in the art and may be present as a fixed combination, anon-fixed combination or kit-of-parts.

A “fixed combination” in the present invention is used as known topersons skilled in the art and is defined as a combination wherein thesaid first active ingredient and the said second active ingredient arepresent together in one unit dosage or in a single entity. One exampleof a “fixed combination” is a pharmaceutical composition wherein thesaid first active ingredient and the said second active ingredient arepresent in admixture for simultaneous administration, such as in aformulation. Another example of a “fixed combination” is apharmaceutical combination wherein the said first active ingredient andthe said second active ingredient are present in one unit without beingin admixture.

A non-fixed combination or “kit-of-parts” in the present invention isused as known to persons skilled in the art and is defined as acombination wherein the said first active ingredient and the said secondactive ingredient are present in more than one unit. One example of anon-fixed combination or kit-of-parts is a combination wherein the saidfirst active ingredient and the said second active ingredient arepresent separately. The components of the non-fixed combination orkit-of-parts may be administered separately, sequentially,simultaneously, concurrently or chronologically staggered. Any suchcombination of a compound of the present invention with an anti-canceragent as defined below is an embodiment of the invention.

The term “(chemotherapeutic) anti-cancer agents”, includes but is notlimited to: 131I-chTNT, abarelix, abiraterone, aclarubicin,ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin,alectinib, alemtuzumab, alendronic acid, alitretinoin, altretamine,amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin,amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumabravtansine, angiotensin II, antithrombin III, aprepitant, arcitumomab,arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine,basiliximab, belotecan, bendamustine, besilesomab, belinostat,bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin,blinatumomab, bortezomib, buserelin, bosutinib, brentuximab vedotin,busulfan, cabazitaxel, cabozantinib, calcitonine, calcium folinate,calcium levofolinate, capecitabine, capromab, carboplatin, carboquone,carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin,ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine,cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid,clofarabine, cobimetinib, copanlisib, crisantaspase, crizotinib,cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin,daratumumab, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin,decitabine, degarelix, denileukin diftitox, denosumab, depreotide,deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride,dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron,doxifluridine, doxorubicin, doxorubicin+estrone, dronabinol, eculizumab,edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, endostatin,enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa,epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib,esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide,everolimus, exemestane, fadrozole, fentanyl, filgrastim,fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide,folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant,gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide,gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine,gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron,granulocyte colony stimulating factor, histamine dihydrochloride,histrelin, hydroxycarbamide, 1-125 seeds, lansoprazole, ibandronic acid,ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib,imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate,interferon alfa, interferon beta, interferon gamma, iobitridol,iobenguane (123I), iomeprol, ipilimumab, irinotecan, Itraconazole,ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lasocholine,lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin,levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin,lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol,melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone,methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone,methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin,mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane,mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphinehydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin,naloxone+pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin,nelarabine, neridronic acid, netupitant/palonosetron,nivolumabpentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab,nimustine, nintedanib, nitracrine, nivolumab, obinutuzumab, octreotide,ofatumumab, olaparib, omacetaxine mepesuccinate, omeprazole,ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin,oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel,palbociclib, palifermin, palladium-103 seed, palonosetron, pamidronicacid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase,PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab,pegfilgrastim, peg interferon alfa-2b, pemetrexed, pentazocine,pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab,picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin,poliglusam, polyestradiol phosphate, polyvinylpyrrolidone+sodiumhyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium,pralatrexate, prednimustine, prednisone, procarbazine, procodazole,propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride,radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab,ranimustine, rasburicase, razoxane, refametinib, regorafenib, risedronicacid, rhenium-186 etidronate, rituximab, rolapitant, romidepsin,romiplostim, romurtide, roniciclib, samarium (153Sm) lexidronam,sargramostim, satumomab, secretin, siltuximab, sipuleucel-T, sizofiran,sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol,streptozocin, sunitinib, talaporfin, talimogene laherparepvec,tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium(99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur,tegafur+gimeracil+oteracil, temoporfin, temozolomide, temsirolimus,teniposide, testosterone, tetrofosmin, thalidomide, thiotepa,thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan,toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab,trastuzumab emtansine, treosulfan, tretinoin, trifluridine+tipiracil,trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin,tryptophan, ubenimex, valatinib, valrubicin, vandetanib, vapreotide,vemurafenib, vinblastine, vincristine, vindesine, vinflunine,vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glassmicrospheres, zinostatin, zinostatin stimalamer, zoledronic acid,zorubicin.

It has now been found, and this constitutes the basis of the presentinvention, that said compounds of the present invention have surprisingand advantageous properties.

In particular, said compounds of the present invention have surprisinglybeen found to effectively inhibit Bub1 kinase and may therefore be usedfor the treatment or prophylaxis of diseases of uncontrolled cellgrowth, proliferation and/or survival, inappropriate cellular immuneresponses, or inappropriate cellular inflammatory responses or diseaseswhich are accompanied with uncontrolled cell growth, proliferationand/or survival, inappropriate cellular immune responses, orinappropriate cellular inflammatory responses, particularly in which theuncontrolled cell growth, proliferation and/or survival, inappropriatecellular immune responses, or inappropriate cellular inflammatoryresponses is mediated by Bub1 kinase, such as, for example,haematological tumours, solid tumours, and/or metastases thereof, e.g.leukaemias and myelodysplastic syndrome, malignant lymphomas, head andneck tumours including brain tumours and brain metastases, tumours ofthe thorax including non-small cell and small cell lung tumours,gastrointestinal tumours, endocrine tumours, mammary and othergynaecological tumours, urological tumours including renal, bladder andprostate tumours, skin tumours, and sarcomas, and/or metastases thereof.

The intermediates used for the synthesis of the compounds of the claimsas described below, as well as their use for the synthesis of thecompounds of claims described below, are one further aspect of thepresent invention. Preferred intermediates are the Intermediate Examplesas disclosed below.

General Procedures

The compounds according to the invention can be prepared according tothe following Schemes 1-19.

The Schemes and procedures described below illustrate synthetic routesto the compounds of general formula (I) of the invention and are notintended to be limiting. It is obvious to the person skilled in the artthat the order of transformations as exemplified in the Schemes can bemodified in various ways. The order of transformations exemplified inthe Schemes is therefore not intended to be limiting. In addition,interconversion of any of the substituents, R¹, R², R³, A and E can beachieved before and/or after the exemplified transformations. Thesemodifications can be such as the introduction of protecting groups,cleavage of protecting groups, reduction or oxidation of functionalgroups, halogenation, metallation, substitution or other reactions knownto the person skilled in the art. These transformations include thosewhich introduce a functionality which allows for further interconversionof substituents. Appropriate protecting groups and their introductionand cleavage are well-known to the person skilled in the art (see forexample T. W. Greene and P. G. M. Wuts in Protective Groups in OrganicSynthesis, 3^(rd) edition, Wiley 1999). Specific examples are describedin the subsequent paragraphs.

Scheme 1 Process for the preparation of reagents A, wherein R¹ and R²have the meaning as given for general formula (I) and whereby X¹ is aleaving group, such as, for example, F, Cl, Br, I or aryl sulfonate suchas for example p-toluene sulfonate, or alkyl sulfonate such as forexample methane sulfonate or trifluoromethane sulfonate, arecommercially available or can be synthesized by those skilled in theart. Compounds of general formula (1) can be converted to compounds ofgeneral formula (2) by reduction methods, such as for example, the Birchreduction using either sodium or lithium in liquid ammonia, in atemperature range from −78° C. to room temperature, to furnish generalformula (2). Compounds of general formula (2) can be converted tocompounds of general formula (3) using primarily alkylation methodswhich known to those skilled and are available in the public domain (seethe teachings of Bannwarth et al., Bioorg. Med. Chem. Lett., 1996, 6,1525 and Bandara et al., J. Chem. Soc., Perkin Trans 1, 1982, 1755) tofurnish general formula (3). Compounds of general formula (2) and/orcompounds of general formula (3) can be converted to reagents A, such asfor example, using acidic hydrolysis methods which known to thoseskilled and are available in the public domain (see the teachings ofBannwarth et al., Bioorg. Med. Chem. Lett., 1996, 6, 1525 and Bandara etal., J. Chem. Soc., Perkin Trans 1, 1982, 1755) to furnish Reagent A.Similar such transformations for the preparation of reagents A have beenpreviously reported (EP2617720 A1; WO 2010/46194 A; Austin et al., J.Am. Chem. Soc., 1997, 119, 6461).

Scheme 2 Another process for the preparation of reagents A, wherein R¹and R² have the meaning as given for general formula (I). Compounds ofgeneral formula (4) can be converted to compounds of general formula (5)or general formula (6) by alkylation methods using, such as for example,alkyl esters of malonic acid, such as, for example, dimethyl malonate ordiethyl malonate, under basic conditions to give either general formula(5) or general formula (6). Alternatively, general formula (5) can beisolated and converted to general formula (6) using basic conditions.Compounds of general formula (6) can be converted to Reagents A byhydrolysis of the ester using acidic or basic conditions, preferablybasic conditions, using an preferably an alkali metal hydroxide such as,for example, NaOH or KOH. After this hydrolysis, treatment with acid tofurnish Reagent A. Similar such transformations for the preparation ofreagents A have been previously reported (WO2007/26024 A2; US2014/39203A1).

Scheme 3 Another process for the preparation of reagents A, wherein R¹and R² have the meaning as given for general formula (I). Compounds ofgeneral formula (7) can be converted to Reagents A using basicconditions, such as, for example, NaH, alkali metal alkoxides, tofurnish Reagent A. Similar such transformations for the preparation ofreagents A have been previously reported (WO2011/62964 A1; 1991 U5505653A1; Tamura et al., J. Med. Chem., 1977, 20, 709; Huynh et al., Bioorg.Med. Chem., 2012, 20, 6831).

Scheme 4 Another process for the preparation of reagents A, wherein R¹represents a hydrogen atom and R² represents hydroxyl or R⁷R⁸N— have themeaning as given for general formula (I). Compounds of general formula(8) can be converted to compounds of general formula (9) by usingprotection methods known to those skilled in the art, such as, forexample silyl protecting groups, such as, for example,tert-butyldiphenylsilyl (see for example T. W. Greene and P. G. M. Wutsin Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999).Compounds of general formula (9) can be converted to Reagent A usingoxidation methods, such as for example, CrO₃ under acidic conditions.Similar such transformations for the preparation of reagents A have beenpreviously reported (Seitz et al., Synthesis, 2014, 46, 381).

Scheme 5 Another process for the preparation of reagents A, wherein R¹represents a hydrogen atom and R² represents hydroxyl or R⁷R⁸N— have themeaning as given for general formula (I). Compounds of general formula(10) can be converted to compounds of general formula (11) by usingreduction methods, known to those skilled in the art, such as, forexample rhodium on alumina, under basic conditions (see the teachings ofSmissmann et al., J. Pharm. Sci., 1966, 55, 1101). Compounds of generalformula (11) can be converted to compounds of general formula Reagent Aby using protection methods, such as, for example, silyl protectinggroups, e.g. tert-butyldiphenylsilyl (see for example T. W. Greene andP. G. M. Wuts in Protective Groups in Organic Synthesis, 3rd edition,Wiley 1999).

Scheme 6 Another process for the preparation of reagents A, wherein R¹represents a hydrogen atom and R² represents hydroxyl or R⁷R⁸N— have themeaning as given for general formula (I). Compounds of formula (12,Pollak, Monatshefte fuer Chemie, 1893, 14, 403; Hlasiwetz, JustusLiebigs Annalen der Chemie, 1861, 119, 201; Andrus et al., TetrahedronLett., 2003, 44, 4819) can be converted to compounds of general formula(13) by using by using protection methods, such as, for example,carbamate protecting groups, e.g. tert-butoxy carbonyl (Boc) (see forfurther examples T. W. Greene and P. G. M. Wuts in Protective Groups inOrganic Synthesis, 3rd edition, Wiley 1999 or see the teachings ofHennings et al., Tetrahedron Lett, 1997, 38, 6379 or U.S. Pat. No.4,872,902 A1). Compounds of general formula (13) can be converted tocompounds of general formula Reagent A by using reduction methods,preferably under basic conditions.

Scheme 7 Process for the preparation of reagents C of general formula(14), wherein R⁵ and m have the meaning as given for general formula(I). In addition, interconversion of any of the substituents can beachieved before and/or after the exemplified transformations. Thesemodifications can be such as the introduction of protecting groups,cleavage of protecting groups, reduction or oxidation of functionalgroups, halogenation, metallation, substitution or other reactions knownto the person skilled in the art. These transformations include thosewhich introduce a functionality which allows for further interconversionof substituents. Appropriate protecting groups and their introductionand cleavage are well-known to the person skilled in the art (see forexample T. W. Greene and P. G. M. Wuts in Protective Groups in OrganicSynthesis, 3rd edition, Wiley 1999). Compounds of general formula 14,whereby LG is a leaving group, such as, for example, F, Cl, Br, I oraryl sulfonate such as for example p-toluene sulfonate, or alkylsulfonate such as for example methane sulfonate or trifluoromethanesulfonate, are commercially available or can be synthesized by thoseskilled in the art.

Compounds of general formula (14) can be converted to compounds ofgeneral formula (15) by treatment with a suitable nucleophile, such asfor example, amines, alcohols, metal alkoxides, azides, thiols or metalthiolates, under either basic, neutral, acidic, catalytic conditions,preferably basic conditions, in a suitable solvent or using thenucleophile as solvent, such as, for example, DMF, tetrahydrofuran(THF), in a temperature range from −78° C. to the boiling point o f therespective solvent, preferably the reaction is carried out −10° C. tothe boiling point of the respective solvent, to furnish general formula(15). Such substitution reactions have been previously reported (Clarket al., J. Med. Chem., 2008, 51, 6631-6634; Guo et al., TetrahedronLetts., 2013, 54, 3233-3237; Watterson et al., J. Med. Chem., 2007, 50,3730-3742; Bellale et al., J. Med. Chem., 2014, 57, 6572-6582; Klimesovaet al., Eur. J. Med. Chem., 1996, 31, 389-395; Leroy et al., Synth.Commun., 1997, 27, 2905-2916; LaMattina et al., J. Org. Chem., 1981, 46,4179-4182; Beugelmans et al., Tetrahedron, 1983, 39, 4153-4162).

Compounds of general formula (15) can be converted to compounds ofgeneral formula Reagent C by many reducing methods known to thoseskilled in the art, using numerous different reagents and reactionconditions; such methods and reagents can be carried out with metalhydrides, such as, for example, lithium aluminium hydride in THF(Bullock et al., J. Am. Chem. Soc., 1956,78, 490, Wang et al., J. Org.Chem., 2006,71, 4021-3160), or using zinc in acetic acid (Rabe, Chem.Ber., 1913, 46, 1024), or using diborane (De Munno et al., Heterocycles,1996, 43, 1893-1900), or using catalytic hydrogenation methods, forexample, hydrogen and palladium on carbon under acidic conditions(Stokker et al., J. Med. Chem., 1981, 24, 115-117; Bertini et al., J.Med. Chem., 2005, 48, 664-670), hydrogen and nickel under basicconditions (Walpole et al., J. Med. Chem., 1993, 36, 2362-2372,Kuramochi et al., Bioorg. Med. Chem., 2005, 13, 4022-4036.)

Scheme 8 Route for the preparation of compounds of general formula (I),wherein R¹, R², R³, A and E have the meaning as given for generalformula (I), supra. In addition, interconversion of any of thesubstituents, R¹, R², R³, A and E can be achieved before and/or afterthe exemplified transformations. These modifications can be such as theintroduction of protecting groups, cleavage of protecting groups,reduction or oxidation of functional groups, halogenation, metallation,substitution or other reactions known to the person skilled in the art.These transformations include those which introduce a functionalitywhich allows for further interconversion of substituents. Appropriateprotecting groups and their introduction and cleavage are well-known tothe person skilled in the art (see for example T. W. Greene and P. G. M.Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley1999). Specific examples are described in the subsequent paragraphs.

Reagent A, reagent B, and reagent C are either commercllly available orcan be prepared according to procedures available from the publicdomain, as understandable to the person skilled in the art. Specificexamples are described in the subsequent paragraphs.

A suitably substituted 1,3-dicarbonyl cyclohexane of general formula(reagent A) can be reacted with a suitably substituted isothiocyanate(reagent B), such as, for example, 3,5-dioxocyclohexanecarboxylic acidor 5-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclohexane-1,3-dione ortert-butyl (3-hydroxy-5-oxocyclohex-3-en-1-yl)carbamate, in a suitablesolvent system, such as, for example, acetonitrile, in the presence of asuitable base, such as, for example, triethylamine or DBU, attemperatures ranging from −78° C. to +100° C., preferably the reactionis carried out at 0° C. or +100° C., to furnish general formula (1).Similar reactions have been performed in the literature (Muthusamy, S.et al. J. Heterocyclic Chem., 1991, 28, 759-763; Jagodzinski, S. andWesolowska; H., Polish Journal of Chemistry, 2001, 75, 387-400; Bolvig,S. et al., Journal of Molecular Structure, 1996, 378, 45-59).

Intermediates of general formula (16) can be converted to intermediatesof general formula (17) by reaction with a suitable amine, such as, forexample 4-(aminomethyl)pyridine, in a suitable solvent system, such as,for example, ethanol and ethyl acetate, at a temperature between roomtemperature and the boiling point of the respective solvents, preferablythe reaction is carried out at the boiling point of the respectivesolvents, whereby the water formed in the reaction is removed from thereaction by methods known to those skilled in the art, such as, forexample, azeotropic removal of water (Dean-Stark conditions) or withmolecular sieves, to furnish general formula (17).

Intermediates of general formula (17) are reacted with a base and/oroxidizing reagent, preferably an oxidizing agent, such as, for examplehydrogen peroxide, in a suitable solvent system, such as, for example,methanol, in a temperature range from room temperature to the boilingpoint of the respective solvent, preferably the reaction is carried outat the boiling point of the respective solvent, to furnish compounds ofgeneral formula (I).

Scheme 9 Route for the preparation of compounds of general formula (I),wherein R¹, R², R³, A and E have the meaning as given for generalformula (I), supra. In addition, interconversion of any of thesubstituents, R¹, R², R³, A and E can be achieved before and/or afterthe exemplified transformations. These modifications can be such as theintroduction of protecting groups, cleavage of protecting groups,reduction or oxidation of functional groups, halogenation, metallation,substitution or other reactions known to the person skilled in the art.These transformations include those which introduce a functionalitywhich allows for further interconversion of substituents. Appropriateprotecting groups and their introduction and cleavage are well-known tothe person skilled in the art (see for example T. W. Greene and P. G. M.Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley1999). Specific examples are described in the subsequent paragraphs.

Reagent A, reagent B, and reagent C are either commercially available orcan be prepared according to procedures available from the publicdomain, as understandable to the person skilled in the art. Specificexamples are described in the subsequent paragraphs.

A suitably substituted 1,3-dicarbonyl cyclohexane of general formula(reagent A) could be converted to intermediates of general formula (18)by reaction with a suitable amine, such as, for example4-(aminomethyl)pyridine, in a suitable solvent system, such as, forexample, ethanol and ethyl acetate, at a temperature between roomtemperature and the boiling point of the respective solvents, preferablythe reaction is carried out at the boiling point of the respectivesolvent, whereby the water formed in the reaction is removed from thereaction by methods known to those skilled in the art, such as, forexample, azeotropic removal of water (Dean-Stark conditions) or withmolecular sieves, to furnish general formula (18). Similar reactionshave been performed in the literature (Fowler, F. et al., Angew. Chem.Int. Ed., 2000, 39, 2132-2135).

Intermediates of general formula (18) can be reacted with a suitablysubstituted isothiocyanate (B), such as, for example,3,5-dioxocyclohexanecarboxylic acid or5-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclohexane-1,3-dione ortert-butyl (3-hydroxy-5-oxocyclohex-3-en-1-yl)carbamate, in a suitablesolvent system, such as, for example, acetonitrile, in the presence of asuitable base, such as, for example, triethylamine or DBU, attemperatures ranging from −78° C. to +100° C., preferably the reactionis carried out at 0° C. or +100° C., to furnish general formula (17).

Intermediates of general formula (17) are reacted with a base and/oroxidizing reagent, preferably an oxidizing agent, such as, for examplehydrogen peroxide, in a suitable solvent system, such as, for example,methanol, in a temperature range from room temperature to the boilingpoint of the respective solvent, preferably the reaction is carried outat the boiling point of the respective solvent, to furnish intermediatesof general formula (I).

Scheme 10 Route for the preparation of compounds of general formula (I),wherein R¹, R², R³, A and E have the meaning as given for generalformula (I), supra. In addition, interconversion of any of thesubstituents, R¹, R², R³, A and E can be achieved before and/or afterthe exemplified transformations. These modifications can be such as theintroduction of protecting groups, cleavage of protecting groups,reduction or oxidation of functional groups, halogenation, metallation,substitution or other reactions known to the person skilled in the art.These transformations include those which introduce a functionalitywhich allows for further interconversion of substituents. Appropriateprotecting groups and their introduction and cleavage are well-known tothe person skilled in the art (see for example T. W. Greene and P. G. M.Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley1999). Specific examples are described in the subsequent paragraphs.

Compounds of the formula (I) can also be prepared using the syntheticmethods described in context of Scheme 3. Compounds reagent D andreagent E, are either commercllly available or can be prepared accordingto procedures available from the public domain, as understandable to theperson skilled in the art.

A suitably substituted 1,3-dicarbonyl cyclohexane of general formula(reagent A) could be reacted with suitably substituted compounds ofgeneral formula (reagent D) where X¹ is a suitable leaving group, suchas, for example, bromide, chloride, preferably bromide, in the presenceof an ammonium salt, such as, for example, ammonium acetate, in asuitable solvent, such as, for example, ethanol, in a temperature rangefrom 0° C. to the boiling point of the respective solvent, preferablythe reaction is carried out at room temperature, to furnish generalformula (19). Similar examples for the formation of a pyrrole ring vlthis manner have been previously published using lactams (Anderson, D.R. et al., J. Med. Chem., 2007, 50, 2647-2654; Amici, R. et al., J. Med.Chem., 2008, 51, 487-501; Bargiotti, A. et al., J. Med. Chem., 2009, 52,293-307).

Intermediates of general formula (19) could be reacted with a suitablehalogenating reagent, such as, for example, copper(I) bromide andN-bromosuccinimide, preferably N-bromosuccinimide, in a suitable solventsystem, such as, for example, acetonitrile, in a temperature range from0° C. to the boiling point of the respective solvent, preferably thereaction is carried out at room temperature, to furnish general formula(20). Similar examples for the bromination of pyrroles have beenpreviously published using lactams (Aiello, E. et al., J. HeterocyclicChem., 1982, 19, 977-979; Duranti, A. et al., Bioorg. Med. Chem., 2003,11, 3965-3973).

Intermediates of general formula (20) could be reacted with a suitableprimary amines, such as, for example, primary aromatic amines andprimary amines, preferably primary aromatic amines, such as, for exampleaniline or 3-aminothiophene, in the presence of a base, such as, forexample, lithium bis(trimethylsilyl)amide (LHMDS), in the presence of acatalyst, such as, for example a suitable ligand, preferably2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl(tBuBrettPhos) and in the presence of a pre-catalyst, such as, forexample a palladium pre-catalyst, preferablychloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II)(BrettPhos-PreCat MTBE ether adduct) in a suitable solvent system, suchas, for example, tetrahydrofuran (THF), in a temperature range from 0°C. to the 200° C., preferably the reaction is carrie d out at 80° C., tofurnish compounds of general formula (I).

Scheme 11 Process for the preparation of compounds of general formula(I). In addition, interconversion of any of the substituents can beachieved before and/or after the exemplified transformations. Thesemodifications can be such as the introduction of protecting groups,cleavage of protecting groups, reduction or oxidation of functionalgroups, halogenation, metallation, substitution or other reactions knownto the person skilled in the art. These transformations include thosewhich introduce a functionality which allows for further interconversionof substituents. Appropriate protecting groups and their introductionand cleavage are well-known to the person skilled in the art (see forexample T. W. Greene and P. G. M. Wuts in Protective Groups in OrganicSynthesis, 3rd edition, Wiley 1999).

Compounds of general formula reagent F are commercially available or canbe synthesized by those skilled in the art. Compounds of general formulareagent G are commercially available or can be synthesized by thoseskilled in the art. Compounds of general formula reagent E arecommercially available and have been referred to in the previousSchemes. Compounds of general formula reagent F are converted tocompounds of general formula (21) by treatment with a suitablebrominating agent, such as for example phenyltrimethyammoniumtribromide, in a suitable solvent, such as, for example, tetrahydrofuran(THF), in a temperature range from 0° C. to the boiling point of therespective solvent, preferably the reaction is carried out at roomtemperature, to furnish general formula (21). Such brominations of1,5,6,7-tetrahydro-4H-indol-4-ones have been previously reported(Davies, H. M. L. and Manning, J. R., J. Am. Chem. Soc., 2006, 128,1060-1061; Remers, W. A. and Weiss, M. J., J. Org. Chem., 1971, 36,1241-1247).

Compounds of general formula (21) are then reacted to introduce asuitable protecting group, such as, for example, t-butoxy carbonyl(Boc), onto the pyrrole nitrogen. Reagents for introducing theseprotecting groups are well-known to those skilled in the art (see forexample T. W. Greene and P. G. M. Wuts in Protective Groups in OrganicSynthesis, 3rd edition, Wiley 1999). The compounds of general formula(22) can be reacted with a compound of general formula (G) as mentionedabove, such as, for example, aromatic boronic acids, heteroaromaticboronic acids, aromatic boronic esters, heteroaromatic boronic esters,preferably primary heteroaromatic boronic acids and heteroaromaticboronic esters, such as, pyridin-4-ylboronic acid and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, in the presenceof a base, such as, for example, caesium carbonate, in the presence of acatalyst, such as, for example a palladium catalyst, preferablybis-(triphenylphosphine)palladium(II) dichloride in a suitable solventsystem, such as, for example, dimethoxyethane and water, in atemperature range from room temperature to the boiling point of therespective solvent, preferably the reaction is carried out at 80-100°C., to furnish compounds of general formula (23).

Alternatively compounds of general formula (21) can be reacted with acompound of general formula (reagent G) as mentioned above, such as, forexample, aromatic boronic acids, heteroaromatic boronic acids, aromaticboronic esters, heteroaromatic boronic esters, preferably primaryheteroaromatic boronic acids and heteroaromatic boronic esters, such as,pyridin-4-ylboronic acid and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, in the presenceof a base, such as, for example, caesium carbonate, in the presence of acatalyst, such as, for example a palladium catalyst, preferablybis-(triphenylphosphine)palladium(II) dichloride in a suitable solventsystem, such as, for example, dimethoxyethane and water, in atemperature range from room temperature to the boiling point of therespective solvent, preferably the reaction is carried out at 80-100°C., to furnish compounds of general formula (19).

Intermediates of general formula (23) can be reacted with a suitablereagent for removing the said protecting group, such methods and theirsuitable reagents for removing these protecting groups are well-known tothose skilled in the art (see for example T. W. Greene and P. G. M. Wutsin Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999). Forexample, with intermediates of general formula (23) where PG is t-butoxycarbonyl (Boc), can be reacted with an acid, such as for example,hydrochloric acid or trifluoroacetic acid (TFA), in a suitable solventsystem, such as, for example, dichloromethane or using the acid assolvent, in a temperature range from 0° C. to the boiling point of therespective solvent, preferably the reaction is carried out at roomtemperature to furnish compounds of general formula (19).

Intermediates of general formula (19) can be reacted with a suitablehalogenating reagent, such as, for example, copper(I) bromide andN-bromosuccinimide, preferably N-bromosuccinimide, in a suitable solventsystem, such as, for example, acetonitrile, in a temperature range from0° C. to the boiling point of the respective solvent, preferably thereaction is carried out at room temperature, to furnish general formula(20). Similar examples for the bromination of pyrroles have beenpreviously published using lactams (Aiello, E. et al., J. HeterocyclicChem., 1982, 19, 977-979; Duranti, A. et al., Bioorg. Med. Chem., 2003,11, 3965-3973).

Intermediates of general formula (20) can be reacted with a suitableprimary amines, such as, for example, primary aromatic amines andprimary amines, preferably primary aromatic amines, such as, for exampleaniline or 3-aminothiophene, in the presence of a base, such as, forexample, lithium bis(trimethylsilyl)amide (LHMDS), in the presence of acatalyst, such as, for example a palladium catalyst, preferably2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl(tBuBrettPhos) in a suitable solvent system, such as, for example,tetrahydrofuran (THF), in a temperature range from 0° C. to the 200° C.,preferably the reaction is carried out at 80° C., to furnish compoundsof general formula (I).

Scheme 12: Route for the preparation of compounds of general formula(Ib), wherein R¹, R², R³, R⁵, A, Q and m have the meaning as given forgeneral formula (I), supra and R¹⁵ represents R⁶—C(O)—, or R⁷R⁸N—C(O)—.

Intermediates of general formula (I-a) are reacted with an acylatingreagent, an acylating agent which can be generated in situ, to furnishcompounds of general formula (I-b). These types of reactions arewell-known (selected literature examples are: S. Miwatashi, et al., J.Med. Chem., 2005, 48, 5966-5979; J. Zhao, et al., Bioorg. Med. Chem.Lett., 2014, 24, 2802-2806; M. P. Hay, et al., J. Med. Chem., 2010, 53,787-797; J. M. Keith, et al., Med. Chem. Lett, 2012, 3, 823-827; J.Liang, et al., Eur. J. Med. Chem., 2013, 67, 175-187).

Not-limiting examples of these types of reagents are:

-   -   i) carboxylic acid with dehydrating reagents typically used in        amide bond formation, such as, for example (HBTU, HATU, PyBOP,        BOP, T3P, EDC, DIC, DCC)    -   ii) acid fluorides, acid chlorides, acid bromides, preferably in        the presence of a base    -   iii) acid anhydrides, preferably in the presence of a base    -   iv) chloroformates, preferably in the presence of a base    -   v) isocyanates, preferably in the presence of a base    -   vi) isothiocyanates, preferably in the presence of a base

Intermediates of general formula (I-a) are reacted with an carbonylcontaining compounds, such as for example, alcohols, aldehydes andketones, preferably aldehydes, in the presence of a reducing agent, tofurnish compounds of general formula (I-b). These types of reactions,also known as reductive aminations, are well-known (selected literatureexamples are: Martinez-Asencio et al., Tetrahedron Letts., 2010, 51,325-327; Martinez-Asencio et al., Org. Biomol. Chem., 2009, 7,2176-2181; Ikeda et al., Eur. J. Med. Chem., 2011, 46, 636-646.

Not-limiting examples of these types of reagents are:

-   -   i) alcohols with 2-aminopyridines in the presence of base, for        example KO^(t)Bu, and copper acetate or nano-Fe₃O₄        (Martinez-Asencio et al., Tetrahedron Letts., 2010, 51, 325-327;        Martinez-Asencio et al., Org. Biomol. Chem., 2009, 7,        2176-2181).    -   ii) Aldehydes with reducing agents, such as for example, sodium        borohydride or sodium cyanoborohydride or sodium        tris(acetoxy)borohydride, preferably in the presence of an acid,        such as acetic acid; Ikeda et al., Eur. J. Med. Chem., 2011, 46,        636-646; Eur. J. Med. Chem., 2000, 35, 815-826; Betzel et al.,        Bioconjugate Chem., 2013, 24, 205-214.    -   iii) Aldehydes under catalytic hydrogenation conditions with a        catalyst, suc as for example Pd/NiO under an H2 atmosphere (Yang        et al., Synth. Commun., 2014, 44, 1314-1322).

Scheme 13 Process for the preparation of compounds of general formula(I-d), wherein R¹, R², R³, A, E have the meaning as given for generalformula (I) and Q represents (═NOH). Compounds of general formula (I-c)wherein Q represents O can be converted to compounds of general formula(I-d) wherein Q represents (═NOH) by treatment with a suitable reagentcontaining one or more NH2 group, such as for example, amines,oxyamines, hydroxylamines, hydrazones or hydrazines, preferablyhydroxylamine, in a suitable solvent, such as, for example, ethanol,methanol, water, DMF, tetrahydrofuran (THF), preferably, ethanol, in atemperature range from −78° C. to the boiling point of the respectivesolvent, preferably the reaction is carried out RT to the boiling pointof the respective solvent, to furnish general formula (I). Suchtransformations have been previously reported (Kesten et al., J. Med.Chem., 1992, 35, 3429-3447; Bisejieks et al., Heteocyclic Comunn., 2005,11, 9-12; Maillard et al., Eur. J. Med. Chem., 1984, 19, 451-456;Hassan, Molecules, 2013, 18, 2683-2711).

Scheme 14 Route for the preparation of compounds of general formula(I-g), wherein R¹, R³, R⁷, R⁸, A, E and Q have the meaning as given forgeneral formula (I), supra. Intermediates of general formula (I-e) arebe hydrolysed under acidic or basic conditions, preferably basiccondidions using an alkali metal hydroxide, such as, for example NaOH tofurnish intermediates of general formula (I-f). Intermediates of generalformula (I-f) are reacted with a nucleophile, preferably amines usingdehydrating reagents, such as, for example, HBTU, HATU, PyBOP, BOP, T3P,EDC, DIC, DCC, to furnish compounds of general formula (I-g), thesetypes of reactions are well-known to those skilled in the art (selectedliterature examples are: Su, et al., J. Nat. Prod., 2001, 64, 466;Sakagami, et al., Chem. Pharm. Bull., 2007, 55, 37; Demont, et al.,Synlett., 2004, 684; Jackson, et al., Bioorg. Med. Chem. Lett., 2002,12, 1093).

Scheme 15 Route for the preparation of compounds of general formula(I-m), wherein R¹, R³, R⁵, R⁷, R⁸, A, E, m and Q have the meaning asgiven for general formula (I), supra and R¹⁵ represents R⁶—C(O)—, orR⁷R⁸N—C(O)—. Intermediates of general formula (I-h) are reacted with anacylating reagent, a sulfonylating reagent or an acylated agent whichcan be generated in situ, to furnish Intermediates of general formula(I-j), these types of reactions are well-known to those skilled in theart (selected literature examples are: S. Miwatashi, et al., J. Med.Chem., 2005, 48, 5966-5979; J. Zhao, et al., Bioorg. Med. Chem. Lett.,2014, 24, 2802-2806; M. P. Hay, et al., J. Med. Chem., 2010, 53,787-797; J. M. Keith, et al., Med. Chem. Lett, 2012, 3, 823-827; J.Liang, et al., Eur. J. Med. Chem., 2013, 67, 175-187; D. Lesuisse, etal., Bioorg. Med. Chem. Lett., 2011, 21, 2224-2228).

Not-limiting examples of these types of reagents can be:

-   -   i) carboxylic acid with dehydrating reagents typically used in        amide bond formation, such as, for example (HBTU, HATU, PyBOP,        BOP, T3P, EDC, DIG, DCC)    -   ii) acid fluorides, acid chlorides, acid bromides, preferably in        the presence of a base    -   iii) acid anhydrides, preferably in the presence of a base    -   iv) chloroformates, preferably in the presence of a base    -   v) isocyanates, preferably in the presence of a base

Intermediates of general formula (I-j) are be hydrolysed under acidic orbasic conditions, preferably basic condidions using an alkali metalhydroxide, such as, for example NaOH to furnish intermediates of generalformula (I-k). Intermediates of general formula (I-k) are reacted withan nucleophile, preferably amines using dehydrating reagents, such as,for example, HBTU, HATU, PyBOP, BOP, T3P, EDC, DIC, DCC, to furnishIntermediates of general formula (I-m), these types of reactions arewell-known to those skilled in the art (selected literature examplesare: Su, et al., J. Nat. Prod., 2001, 64, 466; Sakagami, et al., Chem.Pharm. Bull., 2007, 55, 37; Demont, et al., Synlett., 2004, 684;Jackson, et al., Bioorg. Med. Chem. Lett., 2002, 12, 1093).

Scheme 16 Route for the preparation of compounds of general formula(I-q), wherein R¹, R³, R¹¹, A, E and Q have the meaning as given forgeneral formula (I), supra and LG is a leaving group, such as, forexample, F, Cl, Br, I or aryl sulfonate such as for example p-toluenesulfonate, or alkyl sulfonate such as for example methane sulfonate ortrifluoromethane sulfonate. Intermediates of general formula (I-p) canbe converted to intermediates of general formula (I-q) using methodswell-known to those skilled in the art. (selected literature examplesare: Garro, et al., Eur. J. Med. Chem., 2014, 71, 237; Heathcock, etal., J. Am. Chem. Soc., 1982, 104, 1907; Matsumoto et al., TetrahedronLett., 2000, 41, 8393; Lightner, et al., J. Am. Chem. Soc., 1985, 107,7499; Ryall, et al., Synth. Commun., 1990, 20, 431; Tsuda et al., Chem.Pharm. Bull., 1990, 38, 2136).

Scheme 17 Route for the preparation of compounds of general formula(I-s), wherein R¹, R³, A, E and Q have the meaning as given for generalformula (I), supra and R¹⁶ represents R⁶—C(O)—, R⁶—O—C(O)— orR⁷R⁸N—C(O)—. Intermediates of general formula (I-r) are reacted with anacylating reagent, an acylating agent which can be generated in situ, tofurnish compounds of general formula (I-s). These types of reactions arewell-known (selected literature examples are: S. Miwatashi, et al., J.Med. Chem., 2005, 48, 5966-5979; J. Zhao, et al., Bioorg. Med. Chem.Lett., 2014, 24, 2802-2806; M. P. Hay, et al., J. Med. Chem., 2010, 53,787-797; J. M. Keith, et al., Med. Chem. Lett, 2012, 3, 823-827; J.Liang, et al., Eur. J. Med. Chem., 2013, 67, 175-187).

Not-limiting examples of these types of reagents are:

-   -   i) carboxylic acid with dehydrating reagents typically used in        amide bond formation, such as, for example (HBTU, HATU, PyBOP,        BOP, T3P, EDC, DIC, DCC)    -   ii) acid fluorides, acid chlorides, acid bromides, preferably in        the presence of a base    -   iii) acid anhydrides, preferably in the presence of a base    -   iv) chloroformates, preferably in the presence of a base    -   v) isocyanates, preferably in the presence of a base    -   vi) isothiocyanates, preferably in the presence of a base

Intermediates of general formula (I-r) are reacted with an carbonylcontaining compounds, such as for example, alcohols, aldehydes andketones, preferably aldehydes, in the presence of a reducing agent, tofurnish compounds of general formula (I-s). These types of reactions,also known as reductive aminations, are well-known (selected literatureexamples are: Martinez-Asencio et al., Tetrahedron Letts., 2010, 51,325-327; Martinez-Asencio et al., Org. Biomol. Chem., 2009, 7,2176-2181; Ikeda et al., Eur. J. Med. Chem., 2011, 46, 636-646.

Not-limiting examples of these types of reagents are:

-   -   iv) alcohols with 2-aminopyridines in the presence of base, for        example KO^(t)Bu, and copper acetate or nano-Fe₃O₄        (Martinez-Asencio et al., Tetrahedron Letts., 2010, 51, 325-327;        Martinez-Asencio et al., Org. Biomol. Chem., 2009, 7,        2176-2181).    -   v) Aldehydes with reducing agents, such as for example, sodium        borohydride or sodium cyanoborohydride or sodium        tris(acetoxy)borohydride, preferably in the presence of an acid,        such as acetic acid; Ikeda et al., Eur. J. Med. Chem., 2011, 46,        636-646; Eur. J. Med. Chem., 2000, 35, 815-826; Betzel et al.,        Bioconjugate Chem., 2013, 24, 205-214.    -   vi) Aldehydes under catalytic hydrogenation conditions with a        catalyst, suc as for example Pd/NiO under an H2 atmosphere (Yang        et al., Synth. Commun., 2014, 44, 1314-1322).

Scheme 18 Route for the preparation of compounds of general formula (I),wherein R¹, R², R³, A, E and Q have the meaning as given for generalformula (I).

Compounds of general formula (I-t) can be converted to compounds ofgeneral formula (I) by treatment with a suitable base, such as, forexample, alkali metal carbonate, alkali metal hydrogen carbonate, alkalimetal hydroxide, sodium hydride, alkali metal alkoxide, LHMDS,optionally in the presence of a phase transfer catalyst, or a crownether, with an alkylating reagent which contains a suitable leavinggroup, such as, for example, F, Cl, Br, I or aryl sulfonate such as forexample para-toluene sulfonate, or alkyl sulfonate such as for examplemethane sulfonate or trifluoromethane sulfonate, are commerciallyavailable or can be synthesized by those skilled in the art, in asuitable solvent, such as, for example, ethanol, methanol, water, DMF,tetrahydrofuran (THF), preferably, DMF, in a temperature range from −78°C. to the boiling point o f the respective solvent, preferably thereaction is carried out RT to the boiling point of the respectivesolvent, to furnish general formula (I).

Such transformations have been previously reported (Zhang et al.,Bioorg. Med. Chem. Lett., 2006, 16, 3233-3237; WO2008/132434 A2, Kang etal., Bioorg. Med. Chem., 2010, 18, 6156-6169; Vanotti et al., J. Med.Chem., 2008, 51, 487-501).

Scheme 19 Route for the preparation of compounds of general formula(I-x), wherein R¹, R³, R⁶, A, E and Q have the meaning as given forgeneral formula (I), supra and t is 1 or 2. Intermediates of generalformula (I-v) can be reacted with an oxidizing agent, such as, forexample, meta-chloroperbenzoic acid, hydrogen peroxide, dimethyldioxirane in a suitable solvent system, such as, for example,dichloromethane, chloroform, acetone in a temperature range from −78° C.to the boiling point of the respective solvent, to furnish compounds ofgeneral formula (I-x), these types of reactions are well-known to thoseskilled in the art (selected literature examples are: C. J. Moody etal., Terahedron., 1990, 46, 6525-6544; K. Matsumoto, et al.,Heterocycles, 2008, 76, 191-196).

It is known to the person skilled in the art that, if there are a numberof reactive centers on a starting or intermediate compound, it may benecessary to block one or more reactive centers temporarily byprotective groups in order to allow a reaction to proceed specificallyat the desired reaction center. A detailed description for the use of alarge number of proven protective groups is found, for example, in T. W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, 1999,3rd Ed., or in P. Kocienski, Protecting Groups, Thieme MedicalPublishers, 2000.

The compounds according to the invention are isolated and purified in amanner known per se, e.g. by distilling off the solvent in vacua andrecrystallizing the residue obtained from a suitable solvent orsubjecting it to one of the customary purification methods, such aschromatography on a suitable support material. Furthermore, reversephase preparative HPLC of compounds of the present invention whichpossess a sufficiently basic or acidic functionality, may result in theformation of a salt, such as, in the case of a compound of the presentinvention which is sufficiently basic, a trifluoroacetate or formatesalt for example, or, in the case of a compound of the present inventionwhich is sufficiently acidic, an ammonium salt for example. Salts ofthis type can either be transformed into its free base or free acidform, respectively, by various methods known to the person skilled inthe art, or be used as salts in subsequent biological assays.Additionally, the drying process during the isolation of compounds ofthe present invention may not fully remove traces of cosolvents,especllly such as formic acid or trifluoroacetic acid, to give solvatesor inclusion complexes. The person skilled in the art will recognisewhich solvates or inclusion complexes are acceptable to be used insubsequent biological assays. It is to be understood that the specificform (e.g. salt, free base, solvate, inclusion complex) of a compound ofthe present invention as isolated as described herein is not necessarilythe only form in which said compound can be applied to a biologicalassay in order to quantify the specific biological activity.

Salts of the compounds according to the invention can be obtained bydissolving the free compound in a suitable solvent (for example a ketonesuch as acetone, methylethylketone or methylisobutylketone, an ethersuch as diethyl ether, tetrahydrofuran or dioxane, a chlorinatedhydrocarbon such as methylene chloride or chloroform, or a low molecularweight aliphatic alcohol such as methanol, ethanol or isopropanol) whichcontains the desired acid or base, or to which the desired acid or baseis then added. The acid or base can be employed in salt preparation,depending on whether a mono- or polybasic acid or base is concerned anddepending on which salt is desired, in an equimolar quantitative ratioor one differing therefrom. The salts are obtained by filtering,reprecipitating, precipitating with a non-solvent for the salt or byevaporating the solvent. Salts obtained can be converted into the freecompounds which, in turn, can be converted into salts. In this manner,pharmaceutically unacceptable salts, which can be obtained, for example,as process products in the manufacturing on an industrial scale, can beconverted into pharmaceutically acceptable salts by processes known tothe person skilled in the art. Especially preferred are hydrochloridesand the process used in the example section.

Pure diastereomers and pure enantiomers of the compounds and saltsaccording to the invention can be obtained e.g. by asymmetric synthesis,by using chiral starting compounds in synthesis and by splitting upenantiomeric and diasteriomeric mixtures obtained in synthesis.

Enantiomeric and diastereomeric mixtures can be split up into the pureenantiomers and pure diastereomers by methods known to a person skilledin the art. Preferably, diastereomeric mixtures are separated bycrystallization, in particular fractional crystallization, orchromatography. Enantiomeric mixtures can be separated e.g. by formingdlstereomers with a chiral auxillry agent, resolving the dlstereomersobtained and removing the chiral auxilliary agent. As chiral auxilliaryagents, for example, chiral acids can be used to separate enantiomericbases such as e.g. mandelic acid and chiral bases can be used toseparate enantiomeric acids vl formation of dlstereomeric salts.Furthermore, diastereomeric derivatives such as diastereomeric esterscan be formed from enantiomeric mixtures of alcohols or enantiomericmixtures of acids, respectively, using chiral acids or chiral alcohols,respectively, as chiral auxilliary agents. Additionally, diastereomericcomplexes or diastereomeric clathrates may be used for separatingenantiomeric mixtures. Alternatively, enantiomeric mixtures can be splitup using chiral separating columns in chromatography. Another suitablemethod for the isolation of enantiomers is the enzymatic separation.

One preferred aspect of the invention is the process for the preparationof the compounds of the claims 1 to 5, according to the examples, aswell as the intermediates used for their preparation.

Optionally, compounds of formula (I) according to the invention can beconverted into their salts, or, optionally, salts of the compoundsaccording to the invention can be converted into the free compounds.Corresponding processes are customary for the skilled person.

Commercial Utility

As mentioned supra, the compounds of the present invention havesurprisingly been found to effectively inhibit Bub1 finally resulting incell death e.g. apoptosis and may therefore be used for the treatment orprophylaxis of diseases of uncontrolled cell growth, proliferationand/or survival, inappropriate cellular immune responses, orinappropriate cellular inflammatory responses, or diseases which areaccompanied with uncontrolled cell growth, proliferation and/orsurvival, inappropriate cellular immune responses, or inappropriatecellular inflammatory responses, particularly in which the uncontrolledcell growth, proliferation and/or survival, inappropriate cellularimmune responses, or inappropriate cellular inflammatory responses ismediated by Bub1, such as, for example, benign and malignant neoplasia,more specifically haematological tumours, solid tumours, and/ormetastases thereof, e.g. leukaemias and myelodysplastic syndrome,malignant lymphomas, head and neck tumours including brain tumours andbrain metastases, tumours of the thorax including non-small cell andsmall cell lung tumours, gastrointestinal tumours, endocrine tumours,mammary and other gynaecological tumours, urological tumours includingrenal, bladder and prostate tumours, skin tumours, and sarcomas, and/ormetastases thereof,

especially haematological tumours, solid tumours, and/or metastases ofbreast, bladder, bone, brain, central and peripheral nervous system,cervix, colon, endocrine glands (e.g. thyroid and adrenal cortex),endocrine tumours, endometrium, esophagus, gastrointestinal tumours,germ cells, kidney, liver, lung, larynx and hypopharynx, mesothelioma,ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue,stomach, skin, testis, ureter, vagina and vulva as well as malignantneoplasias including primary tumors in said organs and correspondingsecondary tumors in distant organs (“tumor metastases”). Haematologicaltumors can e.g be exemplified by aggressive and indolnt forms ofleukemia and lymphoma, namely non-Hodgkins disease, chronic and acutemyeloid leukemia (CML/AML), acute lymphoblastic leukemia (ALL), Hodgkinsdisease, multiple myeloma and T-cell lymphoma. Also included aremyelodysplastic syndrome, plasma cell neoplasia, paraneoplasticsyndromes, and cancers of unknown primary site as well as AIDS relatedmalignancies.

A further aspect of the invention is the use of the compounds of formula(I) according to the invention for the treatment of cervical-, breast-,non-small cell lung-, prostate-, colon- and melanoma tumors and/ormetastases thereof, especially preferred for the treatment thereof aswell as a method of treatment of cervical-, breast-, non-small celllung-, prostate-, colon- and melanoma tumors and/or metastases thereofcomprising administering an effective amount of a compound according tothe invention.

One aspect of the invention is the use of the compounds of formula (I)according to the invention for the treatment of cervix tumors as well asa method of treatment of cervix tumors comprising administering aneffective amount of a compound according to the invention.

In accordance with an aspect of the present invention therefore theinvention relates to a compound of formula (I) according to theinvention, or an N-oxide, a salt, a tautomer or a stereoisomer of saidcompound, or a salt of said N-oxide, tautomer or stereoisomerparticularly a pharmaceutically acceptable salt thereof, or a mixture ofsame, as described and defined herein, for use in the treatment orprophylaxis of a disease, especially for use in the treatment of adisease.

Another particular aspect of the present invention is therefore the useof a compound of formula (I) according to the invention, describedsupra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate,or a salt thereof, particularly a pharmaceutically acceptable saltthereof, or a mixture of same, for the prophylaxis or treatment ofhyperproliferative disorders or disorders responsive to induction ofcell death i.e. apoptosis.

The term “inappropriate” within the context of the present invention, inparticular in the context of “inappropriate cellular immune responses,or inappropriate cellular inflammatory responses”, as used herein, is tobe understood as preferably meaning a response which is less than, orgreater than normal, and which is associated with, responsible for, orresults in, the pathology of said diseases.

Preferably, the use is in the treatment or prophylaxis of diseases,especially the treatment, wherein the diseases are haematologicaltumours, solid tumours and/or metastases thereof.

Another aspect is the use of a compound of formula (I) according to theinvention for the treatment of cervical-, breast-, non-small cell lung-,prostate-, colon- and melanoma tumors and/or metastases thereof,especially preferred for the treatment thereof. A preferred aspect isthe use of a compound of formula (I) according to the invention for theprophylaxis and/or treatment of cervical tumors especially preferred forthe treatment thereof.

Another aspect of the present invention is the use of a compoundaccording to the invention or a stereoisomer, a tautomer, an N-oxide, ahydrate, a solvate, or a salt thereof, particularly a pharmaceuticallyacceptable salt thereof, or a mixture of same, as described herein, inthe manufacture of a medicament for the treatment or prophylaxis of adisease, wherein such disease is a hyperproliferative disorder or adisorder responsive to induction of cell death e.g. apoptosis. In anembodiment the disease is a haematological tumour, a solid tumour and/ormetastases thereof. In another embodiment the disease is cervical-,breast-, non-small cell lung-, prostate-, colon- and melanoma tumorand/or metastases thereof, in a preferred aspect the disease is cervicaltumor.

Method of Treating Hyper-Proliferative Disorders

The present invention relates to a method for using the compounds of thepresent invention and compositions thereof, to treat mammalianhyper-proliferative disorders. Compounds can be utilized to inhibit,block, reduce, decrease, etc., cell proliferation and/or cell division,and/or produce cell death e.g. apoptosis. This method comprisesadministering to a mammal in need thereof, including a human, an amountof a compound of this invention, or a pharmaceutically acceptable salt,isomer, polymorph, metabolite, hydrate, solvate or ester thereof; etc.which is effective to treat the disorder. Hyperproliferative disordersinclude but are not limited, e.g., psoriasis, keloids, and otherhyperplasias affecting the skin, benign prostate hyperplasia (BPH),solid tumours, such as cancers of the breast, respiratory tract, brain,reproductive organs, digestive tract, urinary tract, eye, liver, skin,head and neck, thyroid, parathyroid and their distant metastases. Thosedisorders also include lymphomas, sarcomas, and leukaemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem andhypophtalmic glioma, cerebellar and cerebral astrocytoma,medulloblastoma, ependymoma, as well as neuroectodermal and pinealtumour.

Tumours of the male reproductive organs include, but are not limited toprostate and testicular cancer. Tumours of the female reproductiveorgans include, but are not limited to endometrial, cervical, ovarian,vaginal, and vulvar cancer, as well as sarcoma of the uterus.

Tumours of the digestive tract include, but are not limited to anal,colon, colorectal, oesophageal, gallbladder, gastric, pancreatic,rectal, small-intestine, and salivary gland cancers.

Tumours of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, urethral and human papillary renalcancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixedhepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to laryngeal,hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oralcavity cancer and squamous cell. Lymphomas include, but are not limitedto AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-celllymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of thecentral nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

These disorders have been well characterized in humans, but also existwith a similar etiology in other mammals, and can be treated byadministering pharmaceutical compositions of the present invention.

The term “treating” or “treatment” as stated throughout this document isused conventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving thecondition of, etc., of a disease or disorder, such as a carcinoma.

Methods of Treating Kinase Disorders

The present invention also provides methods for the treatment ofdisorders associated with aberrant mitogen extracellular kinaseactivity, including, but not limited to stroke, heart failure,hepatomegaly, cardiomegaly, diabetes, Alzheimer's disease, cysticfibrosis, symptoms of xenograft rejections, septic shock or asthma.

Effective amounts of compounds of the present invention can be used totreat such disorders, including those diseases (e.g., cancer) mentionedin the Background section above. Nonetheless, such cancers and otherdiseases can be treated with compounds of the present invention,regardless of the mechanism of action and/or the relationship betweenthe kinase and the disorder.

The phrase “aberrant kinase activity” or “aberrant tyrosine kinaseactivity,” includes any abnormal expression or activity of the geneencoding the kinase or of the polypeptide it encodes. Examples of suchaberrant activity, include, but are not limited to, over-expression ofthe gene or polypeptide; gene amplification; mutations which produceconstitutively-active or hyperactive kinase activity; gene mutations,deletions, substitutions, additions, etc.

The present invention also provides for methods of inhibiting a kinaseactivity, especially of mitogen extracellular kinase, comprisingadministering an effective amount of a compound of the presentinvention, including salts, polymorphs, metabolites, hydrates, solvates,prodrugs (e.g.: esters) thereof, and diastereoisomeric forms thereof.Kinase activity can be inhibited in cells (e.g., in vitro), or in thecells of a mammalian subject, especially a human patient in need oftreatment.

Methods of Treating Angiogenic Disorders

The present invention also provides methods of treating disorders anddiseases associated with excessive and/or abnormal angiogenesis.

Inappropriate and ectopic expression of angiogenesis can be deleteriousto an organism. A number of pathological conditions are associated withthe growth of extraneous blood vessels. These include, e.g., diabeticretinopathy, ischemic retinal-vein occlusion, and retinopathy ofprematurity [Aiello et al. New Engl. J. Med. 1994, 331, 1480; Peer etal. Lab. Invest. 1995, 72, 638], age-related macular degeneration [AMD;see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855],neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma,inflammation, rheumatoid arthritis (RA), restenosis, in-stentrestenosis, vascular graft restenosis, etc. In addition, the increasedblood supply associated with cancerous and neoplastic tissue, encouragesgrowth, leading to rapid tumour enlargement and metastasis. Moreover,the growth of new blood and lymph vessels in a tumour provides an escaperoute for renegade cells, encouraging metastasis and the consequencespread of the cancer. Thus, compounds of the present invention can beutilized to treat and/or prevent any of the aforementioned angiogenesisdisorders, e.g., by inhibiting and/or reducing blood vessel formation;by inhibiting, blocking, reducing, decreasing, etc. endothelial cellproliferation or other types involved in angiogenesis, as well ascausing cell death e.g. apoptosis of such cell types.

Preferably, the diseases of said method are haematological tumours,solid tumour and/or metastases thereof.

The compounds of the present invention can be used in particular intherapy and prevention i.e. prophylaxis, especially in therapy of tumourgrowth and metastases, especially in solid tumours of all indicationsand stages with or without pre-treatment of the tumour growth.

Pharmaceutical Compositions of the Compounds of the Invention

This invention also relates to pharmaceutical compositions containingone or more compounds of the present invention. These compositions canbe utilised to achieve the desired pharmacological effect byadministration to a patient in need thereof. A patient, for the purposeof this invention, is a mammal, including a human, in need of treatmentfor the particular condition or disease.

Therefore, the present invention includes pharmaceutical compositionsthat are comprised of a pharmaceutically acceptable carrier or auxiliaryand a pharmaceutically effective amount of a compound, or salt thereof,of the present invention.

Another aspect of the invention is a pharmaceutical compositioncomprising a pharmaceutically effective amount of a compound of formula(I) according to the invention and a pharmaceutically acceptableauxiliary for the treatment of a disease mentioned supra, especially forthe treatment of haematological tumours, solid tumours and/or metastasesthereof.

A pharmaceutically acceptable carrier or auxiliary is preferably acarrier that is non-toxic and innocuous to a patient at concentrationsconsistent with effective activity of the active ingredient so that anyside effects ascribable to the carrier do not vitiate the beneficialeffects of the active ingredient. Carriers and auxiliaries are all kindsof additives assisting to the composition to be suitable foradministration.

A pharmaceutically effective amount of compound is preferably thatamount which produces a result or exerts the intended influence on theparticular condition being treated.

The compounds of the present invention can be administered withpharmaceutically-acceptable carriers or auxiliaries well known in theart using any effective conventional dosage unit forms, includingimmediate, slow and timed release preparations, orally, parenterally,topically, nasally, ophthalmically, optically, sublingually, rectally,vaginally, and the like.

For oral administration, the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, lozenges,melts, powders, solutions, suspensions, or emulsions, and may beprepared according to methods known to the art for the manufacture ofpharmaceutical compositions. The solid unit dosage forms can be acapsule that can be of the ordinary hard- or soft-shelled gelatine typecontaining auxiliaries, for example, surfactants, lubricants, and inertfillers such as lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tabletedwith conventional tablet bases such as lactose, sucrose and cornstarchin combination with is binders such as acacia, corn starch or gelatine,disintegrating agents intended to assist the break-up and dissolution ofthe tablet following administration such as potato starch, alginic acid,corn starch, and guar gum, gum tragacanth, acacia, lubricants intendedto improve the flow of tablet granulation and to prevent the adhesion oftablet material to the surfaces of the tablet dies and punches, forexample talc, stearic acid, or magnesium, calcium or zinc stearate,dyes, colouring agents, and flavouring agents such as peppermint, oil ofwintergreen, or cherry flavouring, intended to enhance the aestheticqualities of the tablets and make them more acceptable to the patient.Suitable excipients for use in oral liquid dosage forms includedicalcium phosphate and diluents such as water and alcohols, forexample, ethanol, benzyl alcohol, and polyethylene alcohols, either withor without the addition of a pharmaceutically acceptable surfactant,suspending agent or emulsifying agent. Various other materials may bepresent as coatings or to otherwise modify the physical form of thedosage unit. For instance tablets, pills or capsules may be coated withshellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of anaqueous suspension. They provide the active ingredient in admixture witha dispersing or wetting agent, a suspending agent and one or morepreservatives. Suitable dispersing or wetting agents and suspendingagents are exemplified by those already mentioned above. Additionalexcipients, for example those sweetening, flavouring and colouringagents described above, may also be present.

The pharmaceutical compositions of this invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oilsuch as liquid paraffin or a mixture of vegetable oils. Suitableemulsifying agents may be (1) naturally occurring gums such as gumacacia and gum tragacanth, (2) naturally occurring phosphatides such assoy bean and lecithin, (3) esters or partial esters derived form fattyacids and hexitol anhydrides, for example, sorbitan monooleate, (4)condensation products of said partial esters with ethylene oxide, forexample, polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavouring agents.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil such as, for example, arachis oil, olive oil, sesameoil or coconut oil, or in a mineral oil such as liquid paraffin. Theoily suspensions may contain a thickening agent such as, for example,beeswax, hard paraffin, or cetyl alcohol. The suspensions may alsocontain one or more preservatives, for example, ethyl or n-propylp-hydroxybenzoate; one or more colouring agents; one or more flavouringagents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, and preservative, such asmethyl and propyl parabens and flavouring and colouring agents.

The compounds of this invention may also be administered parenterally,that is, subcutaneously, intravenously, intraocularly, intrasynovially,intramuscularly, or interperitoneally, as injectable dosages of thecompound in preferably a physiologically acceptable diluent with apharmaceutical carrier which can be a sterile liquid or mixture ofliquids such as water, saline, aqueous dextrose and related sugarsolutions, an alcohol such as ethanol, isopropanol, or hexadecylalcohol, glycols such as propylene glycol or polyethylene glycol,glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol, etherssuch as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acidester or, a fatty acid glyceride, or an acetylated fatty acid glyceride,with or without the addition of a pharmaceutically acceptable surfactantsuch as a soap or a detergent, suspending agent such as pectin,carbomers, methycellulose, hydroxypropylmethylcellulose, orcarboxymethylcellulose, or emulsifying agent and other pharmaceuticaladjuvants.

Illustrative of oils which can be used in the parenteral formulations ofthis invention are those of petroleum, animal, vegetable, or syntheticorigin, for example, peanut oil, soybean oil, sesame oil, cottonseedoil, corn oil, olive oil, petrolatum and mineral oil. Suitable fattyacids include oleic acid, stearic acid, isostearic acid and myristicacid. Suitable fatty acid esters are, for example, ethyl oleate andisopropyl myristate. Suitable soaps include fatty acid alkali metal,ammonium, and triethanolamine salts and suitable detergents includecationic detergents, for example dimethyl dialkyl ammonium halides,alkyl pyridinium halides, and alkylamine acetates; anionic detergents,for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether,and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents,for example, fatty amine oxides, fatty acid alkanolamides, andpoly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxidecopolymers; and amphoteric detergents, for example,alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammoniumsalts, as well as mixtures.

The parenteral compositions of this invention will typically containfrom about 0.5% to about 25% by weight of the active ingredient insolution. Preservatives and buffers may also be used advantageously. Inorder to minimise or eliminate irritation at the site of injection, suchcompositions may contain a non-ionic surfactant having ahydrophile-lipophile balance (HLB) preferably of from about 12 to about17. The quantity of surfactant in such formulation preferably rangesfrom about 5% to about 15% by weight. The surfactant can be a singlecomponent having the above HLB or can be a mixture of two or morecomponents having the desired HLB.

Illustrative of surfactants used in parenteral formulations are theclass of polyethylene sorbitan fatty acid esters, for example, sorbitanmonooleate and the high molecular weight adducts of ethylene oxide witha hydrophobic base, formed by the condensation of propylene oxide withpropylene glycol.

The pharmaceutical compositions may be in the form of sterile injectableaqueous suspensions. Such suspensions may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents such as, for example, sodium carboxymethylcellulose,methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents which may be a naturally occurring phosphatide such aslecithin, a condensation product of an alkylene oxide with a fatty acid,for example, polyoxyethylene stearate, a condensation product ofethylene oxide with a long chain aliphatic alcohol, for example,heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxidewith a partial ester derived form a fatty acid and a hexitol such aspolyoxyethylene sorbitol monooleate, or a condensation product of anethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent. Diluents and solvents that may be employed are, for example,water, Ringer's solution, isotonic sodium chloride solutions andisotonic glucose solutions. In addition, sterile fixed oils areconventionally employed as solvents or suspending media. For thispurpose, any bland, fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can be usedin the preparation of injectables.

A composition of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritationexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are, for example, cocoa butter and polyethyleneglycol.

Controlled release formulations for parenteral administration includeliposomal, polymeric microsphere and polymeric gel formulations that areknown in the art.

It may be desirable or necessary to introduce the pharmaceuticalcomposition to the patient via a mechanical delivery device. Theconstruction and use of mechanical delivery devices for the delivery ofpharmaceutical agents is well known in the art. Direct techniques foradministration, for example, administering a drug directly to the brainusually involve placement of a drug delivery catheter into the patient'sventricular system to bypass the blood-brain barrier. One suchimplantable delivery system, used for the transport of agents tospecific anatomical regions of the body, is described in U.S. Pat. No.5,011,472, issued Apr. 30, 1991.

The compositions of the invention can also contain other conventionalpharmaceutically acceptable compounding ingredients, generally referredto as carriers or diluents, as necessary or desired. Conventionalprocedures for preparing such compositions in appropriate dosage formscan be utilized.

Such ingredients and procedures include those described in the followingreferences, each of which is incorporated herein by reference: Powell,M. F. et al., “Compendium of Excipients for Parenteral Formulations” PDAJournal of Pharmaceutical Science & Technology 1998, 52(5), 238-311;Strickley, R. G “Parenteral Formulations of Small Molecule TherapeuticsMarketed in the United States (1999)—Part-1” PDA Journal ofPharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S.et al., “Excipients and Their Use in Injectable Products” PDA Journal ofPharmaceutical Science & Technology 1997, 51(4), 166-171.

Commonly used pharmaceutical ingredients that can be used as appropriateto formulate the composition for its intended route of administrationinclude:

acidifying agents (examples include but are not limited to acetic acid,citric acid, fumaric acid, hydrochloric acid, nitric acid);

alkalinizing agents (examples include but are not limited to ammoniasolution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide,triethanolamine, trolamine);

adsorbents (examples include but are not limited to powdered celluloseand activated charcoa)I;

aerosol propellants (examples include but are not limited to carbondioxide, CCl₂F₂, F₂ClC—CClF₂ and CClF₃)

air displacement agents—examples include but are not limited to nitrogenand argon;

antifungal preservatives (examples include but are not limited tobenzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben,sodium benzoate);

antimicrobial preservatives (examples include but are not limited tobenzalkonium chloride, benzethonium chloride, benzyl alcohol,cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol,phenylmercuric nitrate and thimerosal);

antioxidants (examples include but are not limited to ascorbic acid,ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene,hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate,sodium bisulfite, sodium formaldehyde sulfoxylate, sodiummetabisulfite);

binding materials (examples include but are not limited to blockpolymers, natural and synthetic rubber, polyacrylates, polyurethanes,silicones, polysiloxanes and styrene-butadiene copolymers);

buffering agents (examples include but are not limited to potassiummetaphosphate, dipotassium phosphate, sodium acetate, sodium citrateanhydrous and sodium citrate dihydrate);

carrying agents (examples include but are not limited to acacia syrup,aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orangesyrup, syrup, corn oil, mineral oil, peanut oil, sesame oil,bacteriostatic sodium chloride injection and bacteriostatic water forinjection);

chelating agents (examples include but are not limited to edetatedisodium and edetic acid);

colourants (examples include but are not limited to FD&C Red No. 3, FD&CRed No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&COrange No. 5, D&C Red No. 8, caramel and ferric oxide red);

clarifying agents (examples include but are not limited to bentonite);

emulsifying agents (examples include but are not limited to acacia,cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitanmonooleate, polyoxyethylene 50 monostearate);

encapsulating agents (examples include but are not limited to gelatinand cellulose acetate phthalate),

flavourants (examples include but are not limited to anise oil, cinnamonoil, cocoa, menthol, orange oil, peppermint oil and vanillin);

humectants (examples include but are not limited to glycerol, propyleneglycol and sorbitol);

levigating agents (examples include but are not limited to mineral oiland glycerin);

oils (examples include but are not limited to arachis oil, mineral oil,olive oil, peanut oil, sesame oil and vegetable oil);

ointment bases (examples include but are not limited to lanolin,hydrophilic ointment, polyethylene glycol ointment, petrolatum,hydrophilic petrolatum, white ointment, yellow ointment, and rose waterointment);

penetration enhancers (transdermal delivery) (examples include but arenot limited to monohydroxy or polyhydroxy alcohols, mono- or polyvalentalcohols, saturated or unsaturated fatty alcohols, saturated orunsaturated fatty esters, saturated or unsaturated dicarboxylic acids,essential oils, phosphatidyl derivatives, cephalin, terpenes, amides,ethers, ketones and ureas),

plasticizers (examples include but are not limited to diethyl phthalateand glycerol);

solvents (examples include but are not limited to ethanol, corn oil,cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanutoil, purified water, water for injection, sterile water for injectionand sterile water for irrigation);

stiffening agents (examples include but are not limited to cetylalcohol, cetyl esters wax, microcrystalline wax, paraffin, stearylalcohol, white wax and yellow wax);

suppository bases (examples include but are not limited to cocoa butterand polyethylene glycols (mixtures));

surfactants (examples include but are not limited to benzalkoniumchloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium laurylsulfate and sorbitan mono-palmitate);

suspending agents (examples include but are not limited to agar,bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,kaolin, methylcellulose, tragacanth and veegum);

sweetening agents (examples include but are not limited to aspartame,dextrose, glycerol, mannitol, propylene glycol, saccharin sodium,sorbitol and sucrose);

tablet anti-adherents (examples include but are not limited to magnesiumstearate and talc), tablet binders (examples include but are not limitedto acacia, alginic acid, carboxymethylcellulose sodium, compressiblesugar, ethylcellulose, gelatin, liquid glucose, methylcellulose,non-crosslinked polyvinyl pyrrolidone, and pregelatinized starch);

tablet and capsule diluents (examples include but are not limited todibasic calcium phosphate, kaolin, lactose, mannitol, microcrystallinecellulose, powdered cellulose, precipitated calcium carbonate, sodiumcarbonate, sodium phosphate, sorbitol and starch);

tablet coating agents (examples include but are not limited to liquidglucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetatephthalate and shellac);

tablet direct compression excipients (examples include but are notlimited to dibasic calcium phosphate);

tablet disintegrants (examples include but are not limited to alginicacid, carboxymethylcellulose calcium, microcrystalline cellulose,polacrillin potassium, cross-linked polyvinylpyrrolidone, sodiumalginate, sodium starch glycollate and starch);

tablet glidants (examples include but are not limited to colloidalsilica, corn starch and talc);

tablet lubricants (examples include but are not limited to calciumstearate, magnesium stearate, mineral oil, stearic acid and zincstearate);

tablet/capsule opaquants (examples include but are not limited totitanium dioxide); tablet polishing agents (examples include but are notlimited to carnuba wax and white wax);

thickening agents (examples include but are not limited to beeswax,cetyl alcohol and paraffin);

tonicity agents (examples include but are not limited to dextrose andsodium chloride); viscosity increasing agents (examples include but arenot limited to alginic acid, bentonite, carbomers,carboxymethylcellulose sodium, methylcellulose, polyvinyl pyrrolidone,sodium alginate and tragacanth); and

wetting agents (examples include but are not limited toheptadecaethylene oxycetanol, lecithins, sorbitol monooleate,polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

Pharmaceutical compositions according to the present invention can beillustrated as follows:

Sterile i.v. solution: A 5 mg/mL solution of the desired compound ofthis invention can be made using sterile, injectable water, and the pHis adjusted if necessary. The solution is diluted for administration to1-2 mg/mL with sterile 5% dextrose and is administered as an i.v.infusion over about 60 minutes.

Lyophilised powder for i.v. administration: A sterile preparation can beprepared with (i) 100-1000 mg of the desired compound of this inventionas a lyophilised powder, (ii) 32-327 mg/mL sodium citrate, and (iii)300-3000 mg Dextran 40. The formulation is reconstituted with sterile,injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL,which is further diluted with saline or dextrose 5% to 0.2-0.4 mg/mL,and is administered either IV bolus or by IV infusion over 15-60minutes.

Intramuscular suspension: The following solution or suspension can beprepared, for intramuscular injection:

50 mg/mL of the desired, water-insoluble compound of this invention

5 mg/mL sodium carboxymethylcellulose

4 mg/mL TWEEN 80

9 mg/mL sodium chloride 9 mg/mL benzyl alcohol

Hard Shell Capsules: A large number of unit capsules are prepared byfilling standard two-piece hard galantine capsules each with 100 mg ofpowdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6mg of magnesium stearate.

Soft Gelatin Capsules: A mixture of active ingredient in a digestibleoil such as soybean oil, cottonseed oil or olive oil is prepared andinjected by means of a positive displacement pump into molten gelatin toform soft gelatin capsules containing 100 mg of the active ingredient.The capsules are washed and dried. The active ingredient can bedissolved in a mixture of polyethylene glycol, glycerin and sorbitol toprepare a water miscible medicine mix.

Tablets: A large number of tablets are prepared by conventionalprocedures so that the dosage unit is 100 mg of active ingredient, 0.2mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg ofmicrocrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose.Appropriate aqueous and non-aqueous coatings may be applied to increasepalatability, improve elegance and stability or delay absorption.

Immediate Release Tablets/Capsules: These are solid oral dosage formsmade by conventional and novel processes. These units are taken orallywithout water for immediate dissolution and delivery of the medication.The active ingredient is mixed in a liquid containing ingredient such assugar, gelatin, pectin and sweeteners. These liquids are solidified intosolid tablets or caplets by freeze drying and solid state extractiontechniques. The drug compounds may be compressed with viscoelastic andthermoelastic sugars and polymers or effervescent components to produceporous matrices intended for immediate release, without the need ofwater.

Dose and Administration

Based upon standard laboratory techniques known to evaluate compoundsuseful for the treatment of hyper-proliferative disorders and angiogenicdisorders, by standard toxicity tests and by standard pharmacologicalassays for the determination of treatment of the conditions identifiedabove in mammals, and by comparison of these results with the results ofknown medicaments that are used to treat these conditions, the effectivedosage of the compounds of this invention can readily be determined fortreatment of each desired indication. The amount of the activeingredient to be administered in the treatment of one of theseconditions can vary widely according to such considerations as theparticular compound and dosage unit employed, the mode ofadministration, the period of treatment, the age and sex of the patienttreated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered willgenerally range from about 0.001 mg/kg to about 200 mg/kg body weightper day, and preferably from about 0.01 mg/kg to about 20 mg/kg bodyweight per day. Clinically useful dosing schedules will range from oneto three times a day dosing to once every four weeks dosing. Inaddition, “drug holidays” in which a patient is not dosed with a drugfor a certain period of time, may be beneficial to the overall balancebetween pharmacological effect and tolerability. A unit dosage maycontain from about 0.5 mg to about 1500 mg of active ingredient, and canbe administered one or more times per day or less than once a day. Theaverage daily dosage for administration by injection, includingintravenous, intramuscular, subcutaneous and parenteral injections, anduse of infusion techniques will preferably be from 0.01 to 200 mg/kg oftotal body weight. The average daily rectal dosage regimen willpreferably be from 0.01 to 200 mg/kg of total body weight. The averagedaily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kgof total body weight. The average daily topical dosage regimen willpreferably be from 0.1 to 200 mg administered between one to four timesdaily. The transdermal concentration will preferably be that required tomaintain a daily dose of from 0.01 to 200 mg/kg. The average dailyinhalation dosage regimen will preferably be from 0.01 to 100 mg/kg oftotal body weight.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionor a pharmaceutically acceptable salt or ester or composition thereofcan be ascertained by those skilled in the art using conventionaltreatment tests.

Combination Therapies

The compounds of this invention can be administered as the solepharmaceutical agent or in combination with one or more otherpharmaceutical agents where the combination causes no unacceptableadverse effects. Those combined pharmaceutical agents can be otheragents having antiproliferative effects such as for example for thetreatment of haematological tumours, solid tumours and/or metastasesthereof and/or agents for the is treatment of undesired side effects.Thepresent invention relates also to such combinations.

Other anti-hyper-proliferative agents suitable for use with thecomposition of the invention include but are not limited to thosecompounds acknowledged to be used in the treatment of neoplasticdiseases in Goodman and Gilman's The Pharmacological Basis ofTherapeutics (Ninth Edition), editor Molinoff et al., publ. byMcGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated byreference, especially (chemotherapeutic) anti-cancer agents as definedsupra. The combination can be a non-fixed combination or a fixed-dosecombination as the case may be.

Methods of testing for a particular pharmacological or pharmaceuticalproperty are well known to persons skilled in the art.

The example testing experiments described herein serve to illustrate thepresent invention and the invention is not limited to the examplesgiven.

As will be appreciated by persons skilled in the art, the invention isnot limited to the particular embodiments described herein, but coversall modifications of said embodiments that are within the spirit andscope of the invention as defined by the appended claims.

The following examples illustrate the invention in greater detail,without restricting it. Further compounds according to the invention, ofwhich the preparation is not explicitly described, can be prepared in ananalogous way.

The compounds, which are mentioned in the examples and the salts thereofrepresent preferred embodiments of the invention as well as a claimcovering all subcombinations of the residues of the compound of formula(I) according to the invention as disclosed by the specific examples.

The term “according to” within the experimental section is used in thesense that the procedure referred to is to be used “analogously to”.

Experimental Part

The following table lists the abbreviations used in this paragraph andin the Intermediate Examples and Examples section as far as they are notexplained within the text body.

Abbreviation Meaning AcOH acetic acid (ethanoic acid) ACN acetonitrileaq. aqueous Boc t-butoxycarbonyl br broad Cl chemical ionisation ddoublet DAD diode array detector DBU 1,8-Diazabicyclo(5.4.0)undec-7-eneDCM dichloromethane dd double-doublet DIAD diisopropyl(E)-diazene-1,2-dicarboxylate DIPEA N-ethyl-N-isopropylpropan-2-amineDMA Dimethylacetamide DMF N,N-dimethylformamide DMSO dimethyl sulfoxidedt Double-triplet ELSD Evaporative Light Scattering Detector Et₃NN,N-diethylethanamine EtOAc ethyl acetate EtOH ethanol eq. equivalentESI electrospray (ES) ionisation h hour HATU1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium3-oxid hexafluorophosphate HCl Hydrochloric acid HPLC high performanceliquid chromatography KO^(t)Bu Potassium tert-butoxide LC-MS liquidchromatography mass spectrometry m multiplet mCPBA meta-chloroperbenzoicacid min minute MeCN acetonitrile MeOH methanol MS mass spectrometryNaCl Sodium chloride NaHCO₃ Sodium hydrogen carbonate or sodiumbicarbonate NMR nuclear magnetic resonance spectroscopy: chemical shifts(δ) are given in ppm. The chemical shifts were corrected by setting theDMSO signal to 2.50 ppm using unless otherwise stated. PDA Photo DiodeArray Pd/C Palladium on activated charcoal a quartet r.t. or rt or RTroom temperature, typically in a range from 18° C. to 23° C. Rtretention time (as measured either with HPLC or UPLC) in minutes ssinglet SIBX Stabilized 2-iodoxybenzoic acid SM starting material SQDSingle-Quadrupole-Detector t triplet T3P2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6- trioxide TBAFN,N,N-tributylbutan-1-aminium fluoride td Triple-doublet TEAtriethylamine TFA trifluoroacetic acid THF tetrahydrofuran UPLC ultraperformance liquid chromatography

Other abbreviations have their meanings customary per se to the skilledperson.

The various aspects of the invention described in this application areillustrated by the following examples which are not meant to limit theinvention in any way.

A wavy bond

is used in structural formulae to indicate a mixture of stereoisomers atthe corresponding chiral center to which it is attached. Alternatively,a simple bond

may also be used in structural formulae to indicate a mixture ofstereoisomers at the corresponding chiral center to which it isattached. Stereoisomers which have been isolated are identified asIsomer n (e.g. Isomer 1, Isomer 2) should the absolute configuration ofthe chiral center not have been determined. Determination of theabsolute configuration may be performed by methods known to the skilledperson, such as, XRPD of the crystalline enantiomers.

Specific Experimental Descriptions

NMR peak forms in the following specific experimental descriptions arestated as they appear in the spectra, possible higher order effects havenot been considered. Reactions employing microwave irradiation may berun with a Biotage Initator® microwave oven optionally equipped with arobotic unit. The reported reaction times employing microwave heatingare intended to be understood as fixed reaction times after reaching theindicated reaction temperature. The compounds and intermediates producedaccording to the methods of the invention may require purification.Purification of organic compounds is well known to the person skilled inthe art and there may be several ways of purifying the same compound. Insome cases, no purification may be necessary. In some cases, thecompounds may be purified by crystallization. In some cases, impuritiesmay be stirred out using a suitable solvent. In some cases, thecompounds may be purified by chromatography, particularly flash columnchromatography, using for example pre-packed silica gel cartridges, e.g.from Separtis such as (Solute® Flash silica gel or (Solute® Flash NH₂silica gel in combination with a Isolera® autopurifier (Biotage) andeluents such as gradients of e.g. hexane/ethyl acetate or DCM/methanol.In some cases, the compounds may be purified by preparative HPLC usingfor example a Waters autopurifier equipped with a diode array detectorand/or on-line electrospray ionization mass spectrometer in combinationwith a suitable prepacked reverse phase column and eluents such asgradients of water and acetonitrile which may contain additives such astrifluoroacetic acid, formic acid or aqueous ammonia. In some cases,purification methods as described above can provide those compounds ofthe present invention which possess a sufficiently basic or acidicfunctionality in the form of a salt, such as, in the case of a compoundof the present invention which is sufficiently basic, a trifluoroacetateor formate salt for example, or, in the case of a compound of thepresent invention which is sufficiently acidic, an ammonium salt forexample. A salt of this type can either be transformed into its freebase or free acid form, respectively, by various methods known to theperson skilled in the art, or be used as salts in subsequent biologicalassays. It is to be understood that the specific form (e.g. salt, freebase etc) of a compound of the present invention as isolated asdescribed herein is not necessarily the only form in which said compoundcan be applied to a biological assay in order to quantify the specificbiological activity.

The percentage yields reported in the following examples are based onthe starting component that was used in the lowest molar amount. Air andmoisture sensitive liquids and solutions were transferred via syringe orcannula and introduced into reaction vessels through rubber septa.Commercial grade reagents and solvents were used without furtherpurification. The term “concentrated in vacuo” refers to use of a Buchirotary evaporator at a minimum pressure of approximately 15 mm of Hg.All temperatures are reported uncorrected in degrees Celsius (° C.).

In order that this invention may be better understood, the followingexamples are set forth. These examples are for the purpose ofillustration only and are not to be construed as limiting the scope ofthe invention in any manner. All publications mentioned herein areincorporated by reference in their entirety.

Analytical LC-MS conditions

LC-MS-data given in the subsequent specific experimental descriptionsrefer (unless otherwise noted) to the following conditions:

System: Waters Acquity UPLC-MS: Binary Solvent Manager, SampleManager/Organizer, Column Manager, PDA, ELSD, SQD 3001 or ZQ4000 Column:Acquity UPLC BEH C18 1.7 50 × 2.1 mm Solvent: A1 = water + 0.1% vol.formic acid (99%) A2 = water + 0.2% vol. ammonia (32%) B1 = acetonitrileGradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B Flow: 0.8 mL/minTemperature 60° C. Injection: 2.0 μl Detection: DAD scan range 210-400nm -> Peaktable ELSD Methods: MS ESI+, ESI− Switch -> various scanranges (Report Header Method 1: A1 + B1 = C:\MassLynx\Mass_100_1000.flpMethod 2: A1 + B1 = C:\MassLynx\ NH₃_Mass_100_1000.flp

Preparative HPLC Conditions

“Purification by preparative HPLC” in the subsequent specificexperimental descriptions refers to (unless otherwise noted) thefollowing conditions:

Analytics (Pre- and Post Analytics: Method A):

System: Waters Acquity UPLC-MS: Binary Solvent Manager, SampleManager/Organizer, Column Manager, PDA, ELSD, SQD 3001 Column: AcquityBEH C18 1.7 50 × 2.1 mm Solvent: A = water + 0.1% vol. formic acid (99%)B = acetonitrile Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B Flow:0.8 mL/min Temperature: 60° C. Injection: 2.0 μl Detection: DAD scanrange 210-400 nm MS ESI+, ESI−, scan range 160-1000 m/z ELSD Methods:Purify_pre.flp Purify_post.flp

Analytics (Pre- and Post Analytics: Method B):

System: Waters Acquity UPLC-MS: Binary Solvent Manager, SampleManager/Organizer, Column Manager, PDA, ELSD, SQD 3001 Column: AcquityBEH C18 1.7 50 × 2.1 mm Solvent: A = water + 0.2% vol. ammonia (32%) B =acetonitrile Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B Flow: 0.8mL/min Temperature: 60° C. Injection: 2.0 μl Detection: DAD scan range210-400 nm MS ESI+, ESI−, scan range 160-1000 m/z ELSD Methods:Purify_pre.flp Purify_post.flp

Preparative HPLC (Method Acidic):

System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767,CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBridge C18 5 μm 100 × 30 mmSolvent: A = water + 0.1% vol. formic acid (99%) B = acetonitrileGradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/minTemperature: RT Solution: max. 250 mg/2.5 mL dimethyl sufoxide or DMFInjection: 1 × 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+,ESI−, scan range 160-1000 m/z

Preparative HPLC (Method Basic):

System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767,CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBridge C18 5 μm 100 × 30 mmor Chromatorex RP C-18 10 μm 125 * 30 mm Solvent: A = water + 0.2% vol.ammonia (32%) B = acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B,8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: max. 250 mg/2.5mL dimethyl sufoxide or DMF Injection: 1 × 2.5 mL Detection: DAD scanrange 210-400 nm MS ESI+, ESI−, scan range 160-1000 m/z

Preparative HPLC (Method Chiral):

System: Labomatic Pumpe: HD-5000, Labomatic SP-3000, Labocord 5000,Labomatic Labcol Vario 4000, Gilson GX-241, Column: Chiralpak IB 5 μm250 × 30 mm Solvent: A = ACN + 0.1% DEA B = EtOH Flow: 50 mL/minTemperature: RT Detection: MWD 280 nm

Flash Column Chromatography Conditions

“Purification by (flash) column chromatography” as stated in thesubsequent specific experimental descriptions refers to the use of aBiotage Isolera purification system. For technical specifications see“Biotage product catalogue” on www.biotage.com.

EXAMPLES Example 1(6RS)-6-(Hydroxymethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one1-3:(4RS)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-hydroxy-6-oxo-N-phenylcyclohex-1-ene-1-carbothioamide

To a solution of(5RS)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-hydroxycyclohex-2-en-1-one(20.0 g, 52.6 mmol; can be prepared according to EP 2617720) andphenylisothiocyanate (6.29 mL, 52.6 mmol) in MeCN (90 mL) was added DBU(13.3 mL, 89.3 mmol) at 3° C. and the mixture was stirred at RT for 16h. The mixture was concentrated and purified by Biotage (SNAP silica 340g, EtOAc:Hexane) to give the title compound (20.1 g, 74%).

1-2:(4RS)-4-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-6-oxo-N-phenyl-2-[(pyridin-4-ylmethyl)amino]cyclohex-1-ene-1-carbothioamide

A solution of(4RS)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-hydroxy-6-oxo-N-phenylcyclohex-1-ene-1-carbothioamide(3-3; 20.1 g, 39.0 mmol) and 4-(methylamino)pyridine (7.92 mL, 77.9mmol) in DMA (110 mL) was heated at 100° C. for 2 h. The mixture wasconcentrated and purified by Biotage (SNAP silica 340 g, EtOAc:Hexane)to give the title compound (11.0 g, 67%).

1-1:3-Anilino-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture of(4RS)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-oxo-N-phenyl-2-[(pyridin-4-ylmethyl)amino]cyclohex-1-ene-1-carbothioamide(3-2; 11.0 g, 18.2 mmol), SIBX (45%, 11.3 g, 18.2 mmol) in EtOH (540 mL)was stirred at Rt for 16 h. Et₃N (6 mL) were added, the mixture wasconcentrated and purified by Biotage (SNAP silica 375 g, EtOH:DCM) togive the title compound (7.70 g, 74%).

(6RS)-6-(Hydroxymethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture of3-anilino-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(3-1; 10.0 g, 17.5 mmol) and TBAF (22.7 mL, 1M in THF) in THF (250 mL)was stirred at RT for 16 h. EtOAc (1 L) was added, the mixture washedwith sodium hydroxide (2.5% in water), brine and dried over sodiumsulfate. After filtration and removal of the solvent the residue waspurified by Biotage (SNAP silica 340 g, MeOH:DCM) to give the titlecompound (4.31 g, 74%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.20-2.37 (3H), 2.55 (1H), 2.96 (1H),3.44 (2H), 4.76 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.47(2H), 8.41 (2H), 11.91 (1H)

Example 2 tert-Butyl[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamate2-2: tert-Butyl {[(1RS)-3-hydroxy-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-en-1-yl]methyl}carbamate

To a solution of tert-butyl{[(1RS)-3-hydroxy-5-oxocyclohex-3-en-1-yl]methyl}carbamate (1.00 g, 4.14mmol; commercially available from FCH Group Company) andphenylisothiocyanate (496 μL, 4.14 mmol) in MeCN (50 mL) was added DBU(619 μL, 4.14 mmol) and the mixture was stirred at RT for 16 h. Ethylacetate was added, the mixture extracted with hydrochloric acid (1 M),washed with water and brine and dried over sodium sulfate. Afterfiltration the mixture was concentrated and purified by Biotage (SNAPsilica 100 g, EtOAc:Hexane) to give the title compound (353 mg, 23%).

2-1: tert-Butyl({(1RS)-5-oxo-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-en-1-yl}methyl)carbamate

A solution of tert-butyl[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamate(2-2; 353 mg, 938 μmol) and 4-(methylamino)pyridine (228 μL, 2.25 mmol)in EtOH (20 mL) and EtOAc (20 mL) was heated at 90° C. for 6 h. Themixture was concentrated and purified by Biotage (SNAP silica 100 g,EtOAc:Hexane) to give the title compound (84 mg, 19%).

tert-Butyl[(6RS-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamate

A mixture of tert-butyl({(1RS)-5-oxo-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-en-1-yl}methyl)carbamate(2-1; 80 mg, 171 μmol), hydrogen peroxide (34% in water, 31 μL, 343μmol) in DMSO (1 mL) was heated at 90° C. for 16 h. The mixture wasconcentrated and purified by preparative HPLC (basic method) to give thetitle compound (20 mg, 27%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.40 (9H), 2.20-2.33 (2H), 2.59-2.65(2H), 2.92 (1H), 3.04 (2H), 6.57 (2H), 6.83 (1H), 7.04 (3H), 7.42 (1H),7.46 (2H), 8.41 (2H), 11.91 (1H)

Example 3(6RS)-6-[(Benzyloxy)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one3-2:(4RS)-4-[(Benzyloxy)methyl]-2-hydroxy-6-oxo-N-phenylcyclohex-1-ene-1-carbothioamide

To a solution of(5RS)-5-[(benzyloxy)methyl]-3-hydroxycyclohex-2-en-1-one (350 mg, 1.51mmol; can be prepared according to Archie der Pharmazie, 1979, 312 (3),p. 240-247) and phenylisothiocyanate (200 μL, 1.67 mmol) in MeCN (1 mL)was added DBU (300 μL, 2.01 mmol) and the mixture was stirred at RT for18 h. Hydrochloric acid (1 M) was added, the mixture extracted withdiethyl ether, washed with water and brine and dried over sodiumsulfate. After filtration the mixture was concentrated and purified bycolumn chromatography on silica (DCM) to give the title compound (420mg, 76%).

3-1:(4RS)-4-[(Benzyloxy)methyl]-6-oxo-N-phenyl-2-[(pyridin-4-ylmethyl)amino]cyclohex-1-ene-1-carbothioamide

A solution of(4RS)-4-[(benzyloxy)methyl]-2-hydroxy-6-oxo-N-phenylcyclohex-1-ene-1-carbothioamide(3-2; 400 mg, 1.09 mmol) and 4-(methylamino)pyridine (130 mg, 1.20 mmol)in EtOH (2 mL) was heated at 100° C. for 3 h. The mixture wasconcentrated and purified by column chromatography on silica (EtOAc) togive the title compound (340 mg, 68%).

(6RS)-6-[(Benzyloxy)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture of(4RS)-4-[(benzyloxy)methyl]-6-oxo-N-phenyl-2-[(pyridin-4-ylmethyl)amino]cyclohex-1-ene-1-carbothioamide(3-1; 300 mg, 656 μmol), hydrogen peroxide (35% in water, 120 μL, 1.37mmol) in EtOH (1 mL) was heated at 80° C. for 10 minutes. The mixturewas concentrated and purified by column chromatography on silica(EtOAc:diethyl ether) to give the title compound (66 mg, 21%).

¹H NMR (400 MHz, CDCI₃) δ ppm 2.25 (2H), 2.50 (1H), 2.68 (1H), 2.98(1H), 3.41 (2H), 4.45 (2H), 6.51 (2H), 6.56 (1H), 6.97 (2H), 7.20-7.42(8H), 8.34 (2H), 11.83 (1H)

Example 4 tert-Butyl[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]carbamate4-4: tert-Butyl (3,5-dihydroxyphenyl) carbamate

To a stirred solution of 5-aminoresorcinol (75 g, 600 mmol; CAS-No20734-67-2) in THF (1.5 L) was added TEA (102 mL, 720 mmol) at roomtemperature and then (Boc)₂O (130.8 g, 600 mmol) was added slowly dropwise. The reaction mixture was stirred for 16 h at room temperature.After completion of reaction (TLC), the reaction mixture wasconcentrated under vacuum and then water was added to residue, extractedwith ethyl acetate. The combined organic layer was dried over to Na₂SO₄and concentrated to afford the desired product after silicachromatography (68 g, 51%).

4-3: tert-Butyl [(1RS)-3-hydroxy-5-oxocyclohex-3-en-1-yl]carbamate

To a compound 3 (50 g) in 0.1M NaOH solution (500 mL) was added 10% Pd/C(15 g) at room temperature using a Parr apparatus. The reaction mass washydrogenated with H2 (250 psi) at 60 eC for 16 h. After completion ofreaction (TLC), the reaction mixture was filtered through celite bed andfiltrate was extracted with ethyl acetate. The combined organic layerwas dried over to Na₂SO₄ and concentrated to afford crude product. Thesolid residue was recrystallized in diethyl ether to obtained thedesired product (7.0 g, 14%).

4-2: tert-Butyl[(1RS)-3-hydroxy-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-en-1-yl]carbamate

To a solution of tert-butyl[(1RS)-3-hydroxy-5-oxocyclohex-3-en-1-yl]carbamate (4-3; 5.0 g, 22.0mmol) and phenylisothiocyanate (2.63 mL, 22.0 mmol) in MeCN (50 mL) wasadded DBU (7.50 mL, 50.3 mmol) at 3° C. and the mixture was stirred a tRT for 64 h. The mixture was concentrated and purified by Biotage (SNAPsilica 340 g, EtOAc:Hexane) to give the title compound (4.02 g, 50%).

4-1: tert-Butyl{(1RS)-5-oxo-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-en-1-yl}carbamate

A solution of tert-butyl[(1RS)-3-hydroxy-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-en-1-yl]carbamate(4-2; 1.33 g, 3.67 mmol) and 4-(methylamino)pyridine (731 μL, 7.34 mmol)in DMA (10 mL) was heated at 130° C. for 2 h. The mixture wa sconcentrated and purified by Biotage (SNAP silica 100 g, MeOH:DCM) togive the title compound (945 mg, 57%).

tert-Butyl[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]carbamate

A mixture of tert-butyl{(1RS)-5-oxo-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-en-1-yl}carbamate(4-1; 940 mg, 2.08 mmol), hydrogen peroxide (34% in water, 374 μL, 4.15mmol) in MeOH (50 mL) was heated at 80° C. for 6 h. The mixture wasconcentrated and purified by Biotage (SNAP silica 100 g, MeOH:DCM) togive the title compound (600 mg, 69%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.41 (9H), 2.39-2.49 (2H), 2.81 (1H),3.15 (1H), 4.02 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.28 (1H), 7.44(1H), 7.46 (2H), 8.42 (2H), 11.97 (1H)

Example 5(6RS)-6-Amino-3-anilino-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-onehydrochloride

A mixture of tert-butyl[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]carbamate(4; 400 mg, 956 μmol) and HCl in dioxane (10 mL, 1M) was stirred at RTfor 1 h. The mixture was concentrated to give the title compound (412mg, crude).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.73 (2H), 3.14 (1H), 3.48 (1H), 3.94(1H), 6.72 (2H), 6.76 (1H), 7.13 (2H), 7.89 (2H), 8.04 (1H), 8.48 (3H),8.63 (2H), 13.16 (1H)

Example 6N-[(6RS)-4-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]cyclopropanecarboxamide

A mixture of4-[(6RS)-6-ammonio-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridiniumchloride (5; 83 mg, 212 μmol) and cyclopropanecarbonyl chloride (39 μL,424 μmol) in pyridine (2 mL) was stirred at RT for 16 h. The mixture wasconcentrated and purified by preparative HPLC (basic Method) to give thetitle compound (26 mg, 32%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.61-0.73 (4H), 1.57 (1H), 2.42-2.56(2H), 2.87 (1H), 3.17 (1H), 4.33 (1H), 6.60 (2H), 6.64 (1H), 7.05 (2H),7.45 (1H), 7.47 (2H), 8.42 (2H), 8.45 (1H), 11.97 (1H)

Example 7(6RS)-4-Oxo-N-phenyl-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide7-2:(1RS)-3-hydroxy-5-oxo-N-phenyl-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxamide

To a solution of methyl(1RS)-3-hydroxy-5-oxocyclohex-3-ene-1-carboxylate (630 mg, 3.70 mmol;commercially available from FCH Group Company) and phenylisothiocyanate(443 μL, 3.72 mmol) in MeCN (5.7 mL) was added DBU (867 μL, 5.81 mmol)at 3° C. and the mixture was stirred at RT for 24 h. The mixture wasconcentrated and purified by Biotage (SNAP silica 100 g, EtOAc:Hexane)to give the title compound (93 mg, 7%).

7-1:(1RS)-5-Oxo-N-phenyl-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-ene-1-carboxamide

A solution of(1RS)-3-hydroxy-5-oxo-N-phenyl-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxamide(7-2; 90 mg, 246 μmol) and 4-(methylamino)pyridine (50 μL, 491 μmol) inDMA (800 μL) was heated at 120° C. for 1.5 h. The mixture wasconcentrated and purified by Biotage (SNAP silica 25 g, MeOH:DCM) togive the title compound (67 mg, 60%).

(6RS)-4-Oxo-N-phenyl-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture of(1RS)-5-oxo-N-phenyl-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-ene-1-carboxamide(7-1; 65 mg, 142 μmol), hydrogen peroxide (34% in water, 26 μL, 285μmol) in MeOH (5 mL) was heated at 80° C. for 16 h. The mixture wasconcentrated and purified by preparative HPLC (basic method) to give thetitle compound (14 mg, 23%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.52-2.57 (2H), 2.65 (1H), 3.14 (2H),6.59 (2H), 6.64 (1H), 7.01-7.09 (3H), 7.32 (2H), 7.46 (1H), 7.48 (2H),7.62 (2H), 8.43 (2H), 10.07 (1H), 12.00 (1H)

Example 8 Methyl(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate8-2: Methyl(1RS)-5-oxo-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-ene-1-carboxylate

To a solution of methyl(1RS)-3-hydroxy-5-oxocyclohex-3-ene-1-carboxylate (630 mg, 3.70 mmol;commercially available from FCH Group Company) and phenylisothiocyanate(443 μL, 3.72 mmol) in MeCN (5.7 mL) was added DBU (867 μL, 5.81 mmol)at 3° C. and the mixture was stirred at RT for 24 h. The mixture wasconcentrated and purified by Biotage (SNAP silica 100 g, EtOAc:Hexane)to give the title compound (216 mg, 19%).

8-1: Methyl(1RS)-5-oxo-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-ene-1-carboxylate

A solution of methyl(1RS)-5-oxo-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-ene-1-carboxylate(8-2; 3.00 g, 9.83 mmol) and 4-(methylamino)pyridine (2.0 mL, 19.6 mmol)in dioxane (15 mL) was heated at 1200 for 1.5 h. The mixture wasconcentrated and purified by Biotage (SNAP silica 340 g, MeOH:DCM) togive the title compound (2.71 g, 70%).

Methyl(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate

A mixture of methyl(1RS)-5-oxo-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-ene-1-carboxylate(8-1; 2.70 mg, 6.83 mmol), hydrogen peroxide (34% in water, 1.23 mL,13.7 mmol) in MeOH (50 mL) was heated at 80° C. for 16 h. The mixturewas concentrated and purified by Biotage (SNAP silica 100 g, MeOH:DCM)to give the title compound (1.42 g, 58%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.56-2.62 (2H), 3.09-3.21 (2H), 3.37(1H), 3.64 (3H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.44-7.49 (3H), 8.42(2H), 12.00 (1H)

Example 9(6RS)-4-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid

A mixture of methyl(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate(8; 2.70 g, 7.47 mmol), potassium hydroxide (29.9 mL, 4M in water), THF(29.7 mL) and MeOH (29.7 mL) was stirred at RT for 10 minutes.Hydrochloric acid (39.8 mL, 3M) was added and the mixture concentrated.The precipitate was washed with water and dried to give the titlecompound (2.52 g, 97%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.60 (2H), 3.17 (2H), 3.27 (1H), 6.63(2H), 6.69 (1H), 7.08 (2H), 7.63 (2H), 7.77 (1H), 8.50 (2H), 12.39 (1H),12.65 (1H)

Example 10(6RS)—N-Methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 50 mg, 144 μmol), DMF (2 mL), DIPEA (75 μL, 432 μmol),N-methanamine (216 μL, 2M in THF) and T3P (130 μL, 50% in DMF) wasstirred at RT for 3 days. The mixture was concentrated, EtOAc was added,washed with sodium hydrogencarbonate, filtered and dried to give thetitle compound (40 mg, 73%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.38 (1H), 2.55 (1H), 2.61 (3H),2.95-3.11 (3H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.45 (2H), 7.48 (1H),7.95 (1H), 8.41 (2H), 11.97 (1H)

Example 11(6RS)-4-Oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 47 mg, 134 μmol), DMF (2 mL), DIPEA (70 μL, 401 μmol),propan-1-amine (33 μL, 402 μmol) and T3P (121 μL, 50% in DMF) wasstirred at RT for 2 h. The mixture was concentrated, DCM was added,washed with sodium hydrogencarbonate, filtered and dried to give thetitle compound (34 mg, 61%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.86 (3H), 1.42 (2H), 2.38 (1H), 2.55(1H), 2.95-3.11 (5H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.45 (2H), 7.47(1H), 7.98 (1H), 8.42 (2H), 11.97 (1H)

Example 12(6RS)-4-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 50 mg, 144 μmol), DMF (2 mL), DIPEA (75 μL, 432 μmol), ammonia(863 μL, 0.5 M in water) and T3P (130 μL, 50% in DMF) was stirred at RTfor 3 days. The mixture was concentrated, EtOAc was added, washed withsodium hydrogencarbonate, filtered and dried to give the title compound(40 mg, 76%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.41 (1H), 2.54 (1H), 2.98-3.11 (3H),6.58 (2H), 6.63 (1H), 7.01 (1H), 7.04 (2H), 7.44 (1H), 7.47 (2H), 7.49(1H), 8.41 (2H), 12.00 (1H)

Example 13(6RS)—N-(2-Hydroxyethyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 50 mg, 144 μmol), DMF (2 mL), DIPEA (75 μL, 432 μmol),N-methanamine (216 μL, 2M in THF) and T3P (65 μL, 50% in DMF) wasstirred at RT for 2 h. The mixture was concentrated, washed with sodiumhydrogencarbonate, filtered and dried to give the title compound (34 mg,54%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.38 (1H), 2.54 (1H), 2.97-3.19 (5H),3.41 (2H), 4.75 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.47(2H), 8.07 (1H), 8.41 (2H), 12.07 (1H)

Example 14 Methyl(6RS)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate14-1: methyl(1RS)-3-{[(3-fluoropyridin-4-yl)methyl]amino}-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate

A solution of methyl(1RS)-5-oxo-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-ene-1-carboxylate(8-2; 900 mg, 2.95 mmol) and 1-(3-fluoropyridin-4-yl)methanamine (630μL, 5.89 mmol) in DMA (9 mL) was heated at 120° C. for 1.5 h. Themixture was concentrated and purified by Biotage (SNAP silica 100 g,MeOH:DCM) to give the title compound (524 mg, 41%).

Methyl(6RS)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate

A mixture of methyl(1RS)-3-{[(3-fluoropyridin-4-yl)methyl]amino}-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate(14-1; 500 mg, 1.21 mmol), hydrogen peroxide (34% in water, 218 μL, 2.42mmol) in MeOH (25 mL) was heated at 80° C. for 2 h. The mixture wasconcentrated and purified by Biotage (SNAP silica 50 g, MeOH:DCM) togive the title compound (230 mg, 50%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.61 (2H), 3.15 (2H), 3.39 (1H), 3.65(3H), 6.55 (2H), 6.60 (1H), 6.99 (2H), 7.40 (1H), 7.55 (1H), 8.25 (1H),8.51 (1H), 11.73 (1H)

Example 15 Methyl(6RS)-2-(3-methoxypyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate15-1: methyl(1RS)-3-{[(3-methoxypyridin-4-yl)methyl]amino}-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate

A solution of methyl(1RS)-5-oxo-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-ene-1-carboxylate(8-2; 900 mg, 2.95 mmol) and 1-(3-methoxypyridin-4-yl)methanamine (814mg, 5.89 mmol) in DMA (9 mL) was heated at 120° C. for 1.5 h. Themixture was concentrated and purified by Biotage (SNAP silica 100 g,MeOH:DCM) to give the title compound (754 mg, 57%).

Methyl(6RS)-2-(3-methoxypyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate

A mixture of methyl(1RS)-3-{[(3-methoxypyridin-4-yl)methyl]amino}-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate(15-1; 720 mg, 1.69 mmol), hydrogen peroxide (34% in water, 305 μL, 3.38mmol) in MeOH (33 mL) was heated at 80° C. for 2 h. The mixture wasconcentrated and purified by Biotage (SNAP silica 50 g, MeOH:DCM) togive the title compound (234 mg, 35%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.59 (2H), 3.11 (1H), 3.20 (1H), 3.36(1H), 3.65 (3H), 3.89 (3H), 6.52 (2H), 6.58 (1H), 6.98 (2H), 7.31 (1H),7.41 (1H), 8.01 (1H), 8.35 (1H), 11.40 (1H)

Example 16(6RS)—N-(2-Methoxyethyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 70 mg, 202 μmol), DMF (2 mL), DIPEA (105 μL, 605 μmol),2-methoxyethanamine (53 μL, 605 μmol) and T3P (181 μL, 50% in DMF) wasstirred at RT for 16 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (45 mg, 53%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.37 (1H), 2.54 (1H), 2.97-3.16 (3H),3.24 (2H), 3.26 (3H), 3.36 (2H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.45(1H), 7.46 (2H), 8.11 (1H), 8.42 (2H), 11.96 (1H)

Example 17(6RS)—N-(2-Hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 70 mg, 202 μmol), DMF (2 mL), DIPEA (105 μL, 605 μmol),2-(methylamino)ethanol (49 μL, 605 μmol) and T3P (181 μL, 50% in DMF)was stirred at RT for 16 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (53 mg, 61%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.30-2.38 (1H), 2.46-2.57 (1H),2.86+3.10 (3H), 2.92-3.07 (2H), 3.28-3.55 (4H), 3.64+3.72 (1H),4.69+4.86 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.42-7.48 (3H), 8.41(2H), 11.96 (1H)

Example 18(6RS)—N-Ethyl-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 70 mg, 202 μmol), DMF (2 mL), DIPEA (105 μL, 605 μmol),N-methylethanamine (52 μL, 605 μmol) and T3P (181 μL, 50% in DMF) wasstirred at RT for 16 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (56 mg, 67%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02+1.13 (3H), 2.25-2.36 (1H),2.46-2.59 (1H), 2.83+3.04 (3H), 2.94 (1H), 3.04 (1H), 3.22-3.47 (2H),3.61 (1H), 6.60 (2H), 6.64 (1H), 7.05 (2H), 7.44 (1H), 7.46 (2H), 8.42(2H), 11.95 (1H)

Example 19(6RS)-6-(Morpholin-4-ylcarbonyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 70 mg, 202 μmol), DMF (2 mL), DIPEA (105 μL, 605 μmol),morpholine (53 μL, 605 μmol) and T3P (181 μL, 50% in DMF) was stirred atRT for 16 h. The mixture was filtered and purified by preparative HPLC(basic method) to give the title compound (65 mg, 73%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.33 (1H), 2.54 (1H), 2.96 (1H), 3.05(1H), 3.48 (2H), 3.58 (6H), 3.66 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H),7.44 (1H), 7.46 (2H), 8.42 (2H), 11.97 (1H)

Example 20(6RS)-3-(Phenylamino)-2-(pyridin-4-yl)-6-(pyrrolidin-1-ylcarbonyl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 70 mg, 202 μmol), DMF (2 mL), DIPEA (105 μL, 605 μmol),pyrrolidine (50 μL, 605 μmol) and T3P (181 μL, 50% in DMF) was stirredat RT for 16 h. The mixture was filtered and purified by preparativeHPLC (basic method) to give the title compound (60 mg, 71%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.79 (2H), 1.89 (2H), 2.36 (1H), 2.52(1H), 2.96 (1H), 3.05 (1H), 3.21-3.32 (2H), 3.44 (1H), 3.52 (2H), 6.59(2H), 6.64 (1H), 7.05 (2H), 7.43 (1H), 7.47 (2H), 8.42 (2H), 11.96 (1H)

Example 21(6RS)-6-(Azetidin-1-ylcarbonyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 70 mg, 202 μmol), DMF (2 mL), DIPEA (105 μL, 605 μmol),azetidine (41 μL, 605 μmol) and T3P (181 μL, 50% in DMF) was stirred atRT for 16 h. The mixture was filtered and purified by preparative HPLC(basic method) to give the title compound (44 mg, 54%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.20 (2H), 2.32 (1H), 2.47 (1H),2.89-3.01 (2H), 3.20 (1H), 3.87 (2H), 4.21 (2H), 6.58 (2H), 6.63 (1H),7.04 (2H), 7.42 (1H), 7.47 (2H), 8.42 (2H), 11.97 (1H)

Example 22(6RS)—N-(Cyclopropylmethyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 70 mg, 202 μmol), DMF (2 mL), DIPEA (105 μL, 605 μmol),1-cyclopropylmethanamine (52 μL, 605 μmol) and T3P (181 μL, 50% in DMF)was stirred at RT for 16 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (57 mg, 67%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.16 (2H), 0.41 (2H), 0.96 (1H), 2.38(1H), 2.56 (1H), 2.95-3.14 (5H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.45(1H), 7.46 (2H), 8.08 (1H), 8.41 (2H), 11.96 (1H)

Example 23(6RS)—N-(Cyclopropylmethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 70 mg, 202 μmol), DMF (2 mL), DIPEA (105 μL, 605 μmol),1-cyclopropyl-N-methylmethanamine (58 μL, 605 μmol) and T3P (181 μL, 50%in DMF) was stirred at RT for 16 h. The mixture was filtered andpurified by preparative HPLC (basic method) to give the title compound(58 mg, 66%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.21+0.26 (2H), 0.44+0.50 (2H), 0.96(1H), 2.26-2.37 (1H), 2.45-2.58 (1H), 2.91+3.11 (3H), 2.92-3.08 (2H),3.21 (1H), 3.31 (1H), 3.65 (1H), 6.60 (2H), 6.64 (1H), 7.05 (2H), 7.44(1H), 7.46 (2H), 8.41 (2H), 11.94 (1H)

Example 24(6RS)—N-Methyl-4-oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-y0-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 70 mg, 202 μmol), DMF (2 mL), DIPEA (105 μL, 605 μmol),N-methylpropan-1-amine (62 μL, 605 μmol) and T3P (181 μL, 50% in DMF)was stirred at RT for 16 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (63 mg, 74%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.81+0.86 (3H), 1.47+1.55 (2H),2.24-2.36 (1H), 2.47-2.59 (2H), 2.83+3.04 (3H), 2.89-3.08 (2H),3.19-3.36 (1H), 3.64 (1H), 6.60 (2H), 6.64 (1H), 7.05 (2H), 7.44 (1H),7.46 (2H), 8.42 (2H), 11.95 (1H)

Example 25(6RS)—N,N-Dimethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 70 mg, 202 μmol), DMF (2 mL), DIPEA (105 μL, 605 μmol),N-methylmethanamine (302 μL, 2M in THF) and T3P (181 μL, 50% in DMF) wasstirred at RT for 16 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (53 mg, 67%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.33 (1H), 2.46 (1H), 2.85 (3H), 2.95(1H), 3.03 (1H), 3.07 (3H), 3.66 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H),7.44 (1H), 7.46 (2H), 8.41 (2H), 11.96 (1H)

Example 26(6RS)—N-Ethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 70 mg, 202 μmol), DMF (2 mL), DIPEA (105 μL, 605 μmol),ethanamine (302 μL, 2M in THF) and T3P (181 μL, 50% in DMF) was stirredat RT for 16 h. The mixture was filtered and purified by preparativeHPLC (basic method) to give the title compound (25 mg, 32%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03 (3H), 2.38 (1H), 2.55 (1H),2.95-3.15 (5H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.45 (1H), 7.47 (2H),7.99 (1H), 8.41 (2H), 11.96 (1H)

Example 27(6RS)—N-tert-Butyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 50 mg, 144 μmol), DMF (2 mL), DIPEA (75 μL, 432 μmol),2-methylpropan-2-amine (45 μL, 432 μmol) and T3P (65 μL, 50% in DMF) wasstirred at RT for 3 days. The mixture was concentrated, sodiumhydrogencarbonate was added, the precipitate filtered and purified bypreparative HPLC (basic method) to give the title compound (5 mg, 8%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27 (9H), 2.33 (1H), 2.50 (1H),2.89-3.10 (3H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.46 (2H),7.59 (1H), 8.41 (2H), 11.95 (1H)

Example 28(6RS)-3-(Phenylamino)-6-(piperidin-1-ylcarbonyl)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 50 mg, 144 μmol), DMF (2 mL), DIPEA (75 μL, 432 μmol),piperidine (43 μL, 432 mmol) and T3P (130 μL, 50% in DMF) was stirred atRT for 3 days. The mixture was concentrated and purified by preparativeHPLC (basic method) to give the title compound (16 mg, 25%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.44 (2H), 1.52 (2H), 1.60 (2H), 2.29(1H), 2.54 (1H), 2.94 (1H), 3.04 (1H), 3.46 (2H), 3.49 (2H), 3.66 (1H),6.59 (2H), 6.64 (1H), 7.05 (2H), 7.43 (1H), 7.46 (2H), 8.41 (2H), 11.95(1H)

Example 29(6RS)-4-Oxo-3-(phenylamino)-N-(propan-2-O—2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 50 mg, 144 μmol), DMF (2 mL), DIPEA (75 μL, 432 μmol),propan-2-amine (37 μL, 432 μmol) and T3P (65 μL, 50% in DMF) was stirredat RT for 3 days. The mixture was concentrated and purified bypreparative HPLC (basic method) to give the title compound (18 mg, 32%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.06 (6H), 2.36 (1H), 2.54 (1H),2.92-3.07 (3H), 3.84 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.45 (1H),7.46 (2H), 7.85 (1H), 8.42 (2H), 11.95 (1H)

Example 30(6RS)-6-(Hydroxymethyl)-6-methyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one30-3:(4RS)-4-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-4-methyl-6-oxo-N-phenyl-2-[(pyridin-4-ylmethyl)amino]cyclohex-1-ene-1-carbothioamide

To a solution of(5RS)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-hydroxy-5-methylcyclohex-2-en-1-one(5.00 g, 12.7 mmol; can be prepared according to Synthesis, 2014, 46(3), 381-386) and phenylisothiocyanate (1.52 mL, 12.7 mmol) in MeCN (25mL) was added DBU (1.89 mL, 12.7 mmol) at 3° C. and the mixture wasstirred at RT for 2.5 days. The mixture was poured into water, extractedwith EtOAc, washed with brine and dried over sodium sulfate. Afterfiltration the mixture was concentrated and purified by Biotage (SNAPsilica 100 g, EtOAc:Hexane) to give the title compound (5.18 g, 77%).

30-2:(4RS)-4-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-4-methyl-6-oxo-N-phenyl-2-[(pyridin-4-ylmethyl)amino]cyclohex-1-ene-1-carbothioamide

A solution of(4RS)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-6-oxo-N-phenyl-2-[(pyridin-4-ylmethyl)amino]cyclohex-1-ene-1-carbothioamide(30-3; 3.33 g, 6.29 mmol) and 4-(methylamino)pyridine (894 μL, 8.80mmol) in DMA (16.7 mL) was heated at 80° C. for 2 h. The mixture wasconcentrated and purified by Biotage (SNAP silica 100 g, EtOAc:Hexane)to give the title compound (1.78 g, 43%).

30-1:(6RS)-3-Anilino-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-methyl-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture of(4RS)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-6-oxo-N-phenyl-2-[(pyridin-4-ylmethyl)amino]cyclohex-1-ene-1-carbothioamide(30-2; 1.41 g, 2.28 mmol), SIBX (45%, 1.70 g, 2.73 mmol) in MeOH (32 mL)and DCM (85 mL) was stirred at RT for 1 h. The mixture was poured intosaturated sodium hydrogencarbonate, extracted with DCM and dried oversodium sulfate. After filtration and concentration the residue waspurified by Biotage (SNAP silica 100 g, EtOAc:DCM) to give the titlecompound (662 mg, 50%).

(6RS)-6-(Hydroxymethyl)-6-methyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture of(6RS)-3-anilino-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-methyl-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(30-1; 3.1 g, 5.29 mmol) and TBAF (7.94 mL, 1M in THF) in THF (75 mL)was stirred at 60° C. for 16 h. EtOAc (1 L) was added, the mixturewashed with sodium hydroxide (2.5% in water), brine and dried oversodium sulfate. After filtration and removal of the solvent the residuewas purified by Biotage (SNAP silica 100 g, MeOH:DCM) to give the titlecompound (800 mg, 41%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.98 (3H), 2.08 (1H), 2.38 (1H), 2.59(1H), 2.97 (1H), 3.27 (2H), 4.89 (1H), 6.57 (2H), 6.63 (1H), 7.04 (2H),7.44 (1H), 7.47 (2H), 8.41 (2H), 11.87 (1H)

Example 31 methyl(6RS)-2-(2-Aminopyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate31-1: methyl(1RS)-3-{[(2-aminopyridin-4-yl)methyl]amino}-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate

A solution of methyl(1RS)-5-oxo-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-ene-1-carboxylate(8-2; 6.00 g, 19.6 mmol) and 4-(aminomethyl)pyridin-2-amine (4.84 g,39.3 mmol) in DMA (30 mL) was heated at 130° C. for 1.5 h. The mixturewas concentrated and purified by Biotage (SNAP silica 340 g, MeOH:DCM)to give the title compound (4.12 g, 51%).

Methyl(6RS)-2-(2-aminopyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate

A mixture of methyl(1RS)-3-{[(2-aminopyridin-4-yl)methyl]amino}-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate(31-1; 4.11 g, 10.0 mmol), hydrogen peroxide (34% in water, 1.81 mL,20.0 mmol) in MeOH (103 mL) was heated at 90° C. for 2 h. The mixturewas concentrated and purified by Biotage (SNAP silica 110 g, MeOH:DCM)to give the title compound (2.40 g, 64%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.52-2.62 (2H), 3.07 (1H), 3.14 (1H),3.33 (1H), 3.34 (3H), 5.76 (2H), 6.55 (2H), 6.57 (1H), 6.60 (1H), 6.68(1H), 7.02 (2H), 7.24 (1H), 7.77 (1H), 11.79 (1H)

Example 32(6RS)-6-(Azidomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one32-1:[(6RS)-3-Anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate

A mixture of(6RS)-6-(hydroxymethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(1; 2.00 g, 6.00 mmol), methanesulfonyl chloride (557 μL, 7.20 mmol) inpyridine (32 mL) was stirred at RT for 4 h. MeOH was added, the mixtureconcentrated and purified by Biotage (SNAP silica 110 g, MeOH:DCM) togive the title compound (2.16 g, 88%).

(6RS)-6-(Azidomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture of[(6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (32-1; 1.00 g, 2.43 mmol), sodium azide (1.58 g, 24.3mmol) in DMA (40 mL) was stirred at 80° C. for 2 days. After filtration,the mixture was concentrated and purified by Biotage (SNAP silica 50 g,MeOH:DCM) to give the title compound (865 mg, 99%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.26-2.40 (2H), 2.45-2.55 (1H), 2.71(1H), 3.02 (1H), 3.51 (2H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H),7.47 (2H), 8.42 (2H), 11.96 (1H)

Example 33(6RS)-6-[(Dimethylamino)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture of[(6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (32-1; 50 mg, 122 μmol), N-methylmethanamine (243 μL,2M in THF) in DMA (1 mL) was stirred at 60° C. for 1 h. The mixture wasconcentrated and purified by preparative TLC (MeOH:DCM) to give thetitle compound (11 mg, 25%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.15 (6H), 2.17-2.24 (2H), 2.27-2.47(3H), 2.58 (1H), 3.01 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H),7.46 (2H), 8.41 (2H), 11.91 (1H)

Example 34(6RS)-6-(Hydroxymethyl)-1-methyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture of(6RS)-6-(hydroxymethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(1; 50 mg, 150 μmol), DIAD (47 μL, 240 μmol), triphenylphosphine (63 mg,240 μmol), MeOH (30 μL, 750 μmol) in THF (3 mL) was stirred at RT for2.5 days. The mixture was concentrated and purified by preparative TLC(MeOH:DCM) to give the title compound (18 mg, 32%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.23-2.37 (3H), 2.64 (1H), 3.02 (1H),3.47 (2H), 3.57 (3H), 4.79 (1H), 6.47 (2H), 6.52 (1H), 6.94 (2H), 7.22(1H), 7.35 (2H), 8.50 (2H)

Example 35(6RS)-6-[tert-Butyl(dimethyl)silyl]oxy-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one35-4: (5RS)-5-hydroxycyclohex-2-en-1-one

A solution of benzene-1,3,5-triol (100 g, 792.96 mmol) and NaOH (31.72g, 792.96 mmol) in H2O (1.5 L) was added Rh—Al (10%, 2 g). The mixturewas stirred for 14 hours at 30° C. under H₂ (60 psi). TLC(DCM:MeOH=15:1) indicated the starting material was consumed completely.The solid was filtered and the filtrate was concentrated. The residuewas purified by silica gel chromatography eluted with DCM:MeOH=10:1 togive crude 5-hydroxycyclohexane-1,3-dione (120 g) as a yellow solid.

1H NMR (400 MHz, CDCl3): δ ppm 4.18-4.15. (m, 1H), 3.35 (s, 3H),2.58-2.52 (m, 2H), 2.35-2.29 (m, 2H).

35-3:(5RS)-5-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxycyclohex-2-en-1-one

To a solution of crude 5-hydroxycyclohexane-1,3-dione (35-4; 130 g) inDMF (800 mL) was added NaH (80.8 g, 2.02 mol) in one portion at −5° C.under N2. The mixture was stirred at −5° C. for 10 min. Then TBSCI(229.39 g, 1.52 mol) in DMF (200 mL) was added at −5° C. The mixture wasstirred for another 14 hr at 15° C. TLC indicated the reactioncompleted. The mixture was cooled to 1° C. and quenched by water at 0°C. The aqueous pha se was extracted with EA (1 L). The aqueous phase wasadjusted to pH 5˜6 with aq. HCl (1M). The solid was filtered to give5-[tert-butyl(dimethyl) silyl]oxycyclohexane-1,3-dione (40 g) as a whitesolid.

1H NMR (400 MHz, CDCI3): δ ppm 4.52-4.50. (m, 1H), 3.49-3.32 (m, 2H),2.81-2.66 (m, 4H), 0.83 (s, 6H), 0.07 (s, 6H).

35-2:(4RS)-4-{[tert-Butyl(dimethyl)silyl]oxy}-2-hydroxy-6-oxo-N-phenylcyclohex-1-ene-1-carbothioamide

To a solution of(5RS)-5-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxycyclohex-2-en-1-one(35-3; 1.00 g, 4.13 mmol) and phenylisothiocyanate (494 μL, 4.13 mmol)in MeCN (10 mL) was added DBU (1.40 mL, 9.38 mmol) at 3° C. and themixture was stirred a t RT for 1 h. The mixture was poured into ice coldwater, acidified with hydrochloric acid, extracted with EtOAc, washedwith brine and dried over sodium sulfate. After filtration the mixturewas concentrated and purified by Biotage (SNAP silica 100 g,EtOAc:Hexane) to give the title compound (386 mg, 25%).

35-1:(4RS)-4-{[tert-Butyl(dimethyl)silyl]oxy}-6-oxo-N-phenyl-2-[(pyridin-4-ylmethyl)amino]cyclohex-1-ene-1-carbothioamide

A solution of(4RS)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxy-6-oxo-N-phenylcyclohex-1-ene-1-carbothioamide(35-2; 235 mg, 622 μmol) and 4-(methylamino)pyridine (124 μL, 1.24 mmol)in EtOH (5 mL) and EtOAc (5 mL) was heated at 90° C. for 6 h. Themixture was concentrated and purified by Biotage (SNAP silica 25 g,EtOAc:Hexane) to give the title compound (113 mg, 39%).

(6RS)-6-[tert-Butyl(dimethyl)sily]oxy-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture of(4RS)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-oxo-N-phenyl-2-[(pyridin-4-ylmethyl)amino]cyclohex-1-ene-1-carbothioamide(35-1; 106 mg, 226 μmol), hydrogen peroxide (34% in water, 41 μL, 453μmol) in EtOH (5 mL) was heated at 90° C. for 2 h. The mixture wasconcentrated and purified by Biotage (SNAP silica 25 g, MeOH:DCM) togive the title compound (70 mg, 71%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.08 (3H), 0.09 (3H), 0.84 (9H), 2.42(1H), 2.55 (1H), 2.86 (1H), 3.17 (1H), 4.48 (1H), 6.57 (2H), 6.62 (1H),7.03 (2H), 7.44 (1H), 7.47 (2H), 8.42 (2H), 11.94 (1H)

Example 36(6RS)-6-(Aminomethyl)-3-(phenylamino)-2-(pyridin-4-y0-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture of(6RS)-6-(azidomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(32; 801 mg, 2.24 mmol), triphenylphosphine (1.31 g, 4.98 mmol) ammonia(4.78 mL, 25% in water) in THF (35 mL) was stirred at RT for 16 h. Themixture was concentrated and purified by Biotage (SNAP silica 28 g,MeOH:DCM) to give the title compound (722 mg, 96%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.13-2.27 (2H), 2.37 (1H), 2.59-2.69(3H), 2.97 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.47 (2H),8.40 (2H), 11.90 (1H)

Example 37(6RS)-1-Ethyl-6-(hydroxymethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture of(6RS)-6-(hydroxymethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(1; 50 mg, 150 μmol), DIAD (47 μL, 240 μmol), triphenylphosphine (63 mg,240 μmol), EtOH (1 mL) in THF (3 mL) was stirred at 80° C. for 2.5 days.The mixture was concentrated and purified by preparative TLC (MeOH:DCM)to give the title compound (6 mg, 10%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15 (3H), 2.21-2.37 (3H), 2.68 (1H),3.04 (1H), 3.48 (2H), 4.00 (2H), 4.79 (1H), 6.45 (2H), 6.51 (1H), 6.93(2H), 7.16 (1H), 7.32 (2H), 8.52 (2H)

Example 39(6RS)-6-Hydroxy-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture of(6RS)-6-[tert-butyl(dimethyl)silyl]oxy-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(35; 64 mg, 148 μmol) and TBAF (295 μL, 1M in THF) in THF (10 mL) wasstirred at RT for 4 h. The mixture was poured into saturated sodiumhydrogencarbonate, extracted with EtOAc, washed with brine and driedover sodium sulfate. After filtration and concentration the residue waspurified by Biotage (SNAP silica 10 g, MeOH:DCM) to give the titlecompound (48 mg, max 100%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.39 (1H), 2.55 (1H), 2.83 (1H), 3.13(1H), 4.29 (1H), 5.20 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.43 (1H),7.46 (2H), 8.41 (2H), 11.92 (1H)

Example 40(6RS)-6-Ethenyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one40-1:(6RS)-3-Anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carbaldehyde

A solution of ethanedioyl dichloride (196 μL, 2.25 mmol) in DCM (6 mL)was cooled to −78° C. DMSO (319 μL, 4.50 mmol) was added slowly followedby a solution of(6RS)-6-(hydroxymethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(1; 300 mg, 900 μmol) in DCM (6 mL) and DMSO (1.2 mL). The mixture wasstirred at −78° C. for 1 h, Et₃N (1.0 mL) was added and the mixturewarmed to RT. Water was added, the mixture extracted with DCM/MeOH anddried over sodium sulfate. After filtration and concentration theresidue was purified by Biotage (SNAP silica 25 g, MeOH:DCM) to give thetitle compound (158 mg, 53%).

(6RS)-6-Ethenyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

To a solution of methyl(triphenyl)phosphonium bromide (270 mg, 754 μmol)in THF (5 mL) was added KO^(t)Bu (85 mg, 754 μmol) at 0° C. and themixture stirred at 0° C. to RT for 0.5 h. A solution of(6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carbaldehyde(40-1; 50 mg, 151 μmol) in THF (2 mL) was added at 0° C. and the mixturestirred for 2 h. Water and EtOAc were added, the mixture washed withsaturated ammonium chloride solution and dried over sodium sulfate.After filtration and concentration the residue was purified bypreparative TLC (MeOH:DCM) to give the title compound (29 mg, 55%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.38 (2H), 2.79 (1H), 2.92-3.05 (2H),5.07 (1H), 5.14 (1H), 5.95 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.45(1H), 7.47 (2H), 8.42 (2H), 11.96 (1H)

Example 411-Ethyl-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylurea

A mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 30 mg, 90 μmol), isocyanatoethane (14 μL, 181 μmol) in pyridine (1mL) was stirred at RT for 16 h. The mixture was concentrated andpurified by preparative TLC (MeOH:DCM) to give the title compound (23mg, 59%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.00 (3H), 2.16-2.35 (3H), 2.60 (1H),2.93 (1H), 2.99-3.08 (3H), 3.13 (1H), 5.81 (1H), 6.04 (1H), 6.57 (2H),6.63 (1H), 7.04 (2H), 7.44 (1H), 7.46 (2H), 8.41 (2H), 11.92 (1H)

Example 421-Cyclopropyl-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylurea

A mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 30 mg, 90 μmol), isocyanatocyclopropane (15 μL, 181 μmol) inpyridine (1 mL) was stirred at RT for 16 h. The mixture was concentratedand purified by preparative TLC (MeOH:DCM) to give the title compound(22 mg, 55%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.35 (2H), 0.58 (2H), 2.17-2.35 (3H),2.41 (1H), 2.60 (1H), 2.93 (1H), 3.04-3.19 (2H), 6.11 (1H), 6.17 (1H),6.58 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.46 (2H), 8.41 (2H), 11.93(1H)

Example 431-[(6RS)-4-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-3-propan-2-ylurea

A mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 30 mg, 90 μmol), 2-isocyanatopropane (18 μL, 181 μmol) in pyridine(1 mL) was stirred at RT for 16 h. The mixture was concentrated andpurified by preparative TLC (MeOH:DCM) to give the title compound (17mg, 42%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03 (3H), 1.04 (3H), 2.16-2.35 (3H),2.59 (1H), 2.92 (1H), 3.02-3.18 (2H), 3.67 (1H), 5.68 (1H), 5.93 (1H),6.57 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.46 (2H), 8.41 (2H), 11.93(1H)

Example 441-(Furan-2-ylmethyl)-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylurea

A mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 30 mg, 90 μmol), 2-(isocyanatomethyl)furan (19 μL, 181 μmol) inpyridine (1 mL) was stirred at RT for 16 h. The mixture was concentratedand purified by preparative TLC (MeOH:DCM) to give the title compound(20 mg, 46%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.17-2.35 (3H), 2.60 (1H), 2.93 (1H),3.05-3.20 (2H), 4.21 (2H), 6.18 (1H), 6.20 (1H), 6.30 (1H), 6.38 (1H),6.57 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.46 (2H), 7.57 (1H), 8.41(2H), 11.94 (1H)

Example 451-(3-Chloro-4-fluorophenyl)-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylurea

A mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 30 mg, 90 μmol), 2-chloro-1-fluoro-4-isocyanatobenzene (22 μL, 181μmol) in pyridine (1 mL) was stirred at RT for 16 h. The mixture wasconcentrated and purified by preparative TLC (MeOH:DCM) to give thetitle compound (23 mg, 48%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.22-2.41 (3H), 2.66 (1H), 2.97 (1H),3.13-3.32 (2H), 6.55 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.24 (1H),7.27 (1H), 7.44 (1H), 7.46 (2H), 7.79 (1H), 8.41 (2H), 8.81 (1H), 11.93(1H)

Example 46 Methyl[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamate

A mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 30 mg, 90 μmol), methyl carbonochloridate (14 μL, 181 μmol) inpyridine (1 mL) was stirred at RT for 2 h. The mixture was concentratedand purified by preparative TLC (MeOH:DCM) to give the title compound(20 mg, 54%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.18-2.38 (3H), 2.62 (1H), 2.94 (1H),3.10 (2H), 3.55 (3H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.34 (1H), 7.43(1H), 7.46 (2H), 8.40 (2H), 11.94 (1H)

Example 47N-[(6RS)-4-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylacetamide

A mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 30 mg, 90 μmol), acetyl chloride (13 μL, 181 μmol) in pyridine (1mL) was stirred at RT for 2 h. The mixture was concentrated and purifiedby preparative TLC (MeOH:DCM) to give the title compound (8 mg, 23%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.85 (3H), 2.22 (1H), 2.28-2.37 (2H),2.61 (1H), 2.93 (1H), 3.11 (1H), 3.19 (1H), 6.57 (2H), 6.63 (1H), 7.04(2H), 7.43 (1H), 7.47 (2H), 8.00 (1H), 8.40 (2H), 11.98 (1H)

Example 48N-[(6RS)-4-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonamide

A mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 30 mg, 90 μmol), methanesulfonyl chloride (14 μL, 181 μmol) inpyridine (1 mL) was stirred at RT for 2 h. The mixture was concentratedand purified by preparative TLC (MeOH:DCM) to give the title compound(13 mg, 3%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.26 (1H), 2.32-2.41 (2H), 2.67 (1H),2.93 (3H), 2.99-3.08 (3H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.22 (1H),7.44 (1H), 7.47 (2H), 8.41 (2H), 11.97 (1H)

Example 49(6RS)-2-(3-Methoxypyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid

A mixture of methyl(6RS)-2-(3-methoxypyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate(15; 291 mg, 743 μmol), potassium hydroxide (2.97 mL, 4M in water), THF(6 mL) and MeOH (6 mL) was stirred at RT for 15 minutes. Hydrochloricacid (4 mL, 3M) was added and the mixture concentrated. The precipitatewas washed with water and dried to give the title compound (215 mg,77%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.55 (1H), 3.06-3.22 (4H), 3.89 (3H),6.52 (2H), 6.58 (1H), 6.98 (2H), 7.30 (1H), 7.42 (1H), 8.01 (1H), 8.34(1H), 11.38 (1H), 12.61 (1H)

Example 50 Methyl(6RS)-2-[2-(acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate

A mixture of methyl(6RS)-2-(2-aminopyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate(31; 177 mg, 470 μmol), acetyl chloride (67 μL, 940 μmol) in pyridine (5mL) and THF (0.5 mL) was stirred at RT for 1 h. MeOH was added, themixture concentrated and purified by Biotage (SNAP silica 50 g,MeOH:DCM) to give the title compound (161 mg, 82%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.07 (3H), 2.58 (2H), 3.11 (1H), 3.18(1H), 3.34 (1H), 3.64 (3H), 6.55 (2H), 6.60 (1H), 7.01 (2H), 7.15 (1H),7.37 (1H), 8.09 (1H), 8.23 (1H), 10.36 (1H), 12.01 (1H)

Example 51(4E/Z)-5-[(6RS)-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]pent-4-enoicacid

To a solution of (3-carboxypropyl)(triphenyl)phosphonium bromide (324mg, 754 μmol) in THF (5 mL) was added KO^(t)Bu (169 mg, 1.51 mmol) at 0°C. and the mixture stirred at 0° C. to RT for 0.5 h. A solution of(6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carbaldehyde(40-1; 50 mg, 151 μmol) in THF (2 mL) was added at 0° C. and the mixturestirred for 2 h. Water and EtOAc were added, the mixture washed withbrine and dried over sodium sulfate. After filtration and concentrationthe residue was purified by preparative TLC (MeOH:DCM) to give the titlecompound (27 mg, 42%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.15-2.37 (6H), 2.71 (1H), 2.93 (1H),3.26 (1H), 5.40 (2H), 6.59 (2H), 6.63 (1H), 7.04 (2H), 7.43 (1H), 7.49(2H), 8.40 (2H), 12.17 (1H)

Example 52(6RS)-2-(3-Fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid

A mixture of methyl(6RS)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate(14; 222 mg, 585 μmol), potassium hydroxide (2.34 mL, 4M in water), THF(5 mL) and MeOH (5 mL) was stirred at RT for 15 minutes. Hydrochloricacid (3.1 mL, 3M) was added and the mixture concentrated. Theprecipitate was washed with water and dried to give the title compound(185 mg, 85%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.42-2.62 (3H), 3.10 (2H), 6.55 (2H),6.60 (1H), 6.99 (2H), 7.39 (1H), 7.56 (1H), 8.24 (1H), 8.50 (1H), 11.67(1H)

Example 53(6RS)-6-[(E/Z)-2-(4-Fluorophenyl)ethenyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

To a solution of (4-fluorobenzyl)(triphenyl)phosphonium bromide (340 mg,754 μmol) in THF (5 mL) was added KO^(t)Bu (85 mg, 754 μmol) at 0° C.and the mixture stirred at 0° C. to RT for 0.5 h. A solution of(6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carbaldehyde(40-1; 50 mg, 151 μmol) in THF (2 mL) was added at 0° C. and the mixturestirred for 2 h. Water and EtOAc were added, the mixture washed withbrine and dried over sodium sulfate. After filtration and concentrationthe residue was purified by preparative TLC (MeOH:DCM) to give the titlecompound (34 mg, 50%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.30-2.53 (2H), 2.83-2.93 (1H),2.96-3.48 (2H), 5.73+6.37 (1H), 6.47-6.65 (4H), 7.04 (2H), 7.14-7.22(2H), 7.35 (1H), 7.43-7.50 (4H), 8.39-8.44 (2H), 11.99 (1H)

Example 54(6RS)-6-(Morpholin-4-ylmethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture of[(6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (32-1; 50 mg, 122 μmol), morpholine (53 μL, 608 μmol)in DMA (1.5 mL) was stirred at 100° C. for 2 h. The mixture wasconcentrated and purified by preparative HPLC (basic method) to give thetitle compound (15 mg, 30%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.20 (1H), 2.26-2.45 (7H), 2.47-2.56(1H), 2.60 (1H), 3.05 (1H), 3.59 (4H), 6.58 (2H), 6.63 (1H), 7.04 (2H),7.44 (1H), 7.46 (2H), 8.41 (2H), 11.91 (1H)

Example 55(6RS)-6-[Methyl(propan-2-yl)amino]methyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture of[(6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (32-1; 50 mg, 122 μmol), N-methylpropan-2-amine (101μL, 972 μmol) in DMA (1.5 mL) was stirred at 100° C. for 4 h. Themixture was concentrated and purified by preparative HPLC (basic method)to give the title compound (15 mg, 29%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.93 (6H), 2.15 (3H), 2.17 (1H),2.27-2.41 (4H), 2.59 (1H), 2.75 (1H), 3.02 (1H), 6.58 (2H), 6.63 (1H),7.04 (2H), 7.43 (1H), 7.46 (2H), 8.40 (2H), 11.89 (1H)

Example 56(6RS)-6-[(1E/Z)-3-(Dimethylamino)prop-1-en-1-yl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

To a solution of [2-(dimethylamino)ethyl](triphenyl)phosphonium bromide(688 mg, 1.66 mmol) in THF (11 mL) was added KO^(t)Bu (186 mg, 1.66mmol) at 0° C. and the mixture stirred at 0° C. to RT for 0.5 h. Asolution of(6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carbaldehyde(40-1; 110 mg, 332 μmol) in THF (5 mL) was added at 0° C. and themixture stirred for 2 h. Water was added, the mixture extracted withEtOAc, washed with brine and dried over sodium sulfate. After filtrationand concentration the residue was purified by Biotage (SNAP silica 28 g,MeOH:DCM) to give the title compound (49 mg, 38%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.13 (6H), 2.22 (1H), 2.37 (1H), 2.75(1H), 2.85-2.95 (3H), 3.28 (1H), 5.47 (1H), 5.57 (1H), 6.59 (2H), 6.64(1H), 7.05 (2H), 7.44 (1H), 7.47 (2H), 8.41 (2H), 11.94 (1H)

Example 571-[(6RS)-4-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-3-(2RS)-(tetrahydrofuran-2-ylmethyl)urea

A mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 30 mg, 90 μmol), (2RS)-2-(isocyanatomethyl)tetrahydrofuran (21 μL,181 μmol) in pyridine (1 mL) was stirred at RT for 16 h. The mixture wasconcentrated and purified by preparative TLC (MeOH:DCM) to give thetitle compound (28 mg, 61%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48 (1H), 1.74-1.90 (3H), 2.16-2.33(3H), 2.59 (1H), 2.92 (1H), 2.96-3.19 (4H), 3.61 (1H), 3.72-3.83 (2H),5.91 (1H), 6.15 (1H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.46(2H), 8.41 (2H), 11.93 (1H)

Example 58N-Methyl-4-oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamideIsomer 1

(6RS)—N-methyl-4-oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide (24; 20.5 mg, 51 μmol) were separated bypreparative HPLC (chiral method) to give the title compound (8 mg, 39%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.81+0.86 (3H), 1.47+1.55 (2H),2.24-2.36 (1H), 2.47-2.59 (2H), 2.83+3.04 (3H), 2.89-3.08 (2H),3.19-3.36 (1H), 3.64 (1H), 6.60 (2H), 6.64 (1H), 7.05 (2H), 7.44 (1H),7.46 (2H), 8.42 (2H), 11.95 (1H)

Example 59N,N-Dimethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamideIsomer 1

(6RS)—N,N-dimethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide(25; 110 mg, 294 μmol) were separated by preparative HPLC (chiralmethod) to give the title compound (41 mg, 37%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.33 (1H), 2.46 (1H), 2.85 (3H), 2.95(1H), 3.03 (1H), 3.07 (3H), 3.66 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H),7.44 (1H), 7.46 (2H), 8.41 (2H), 11.96 (1H)

Example 60N,N-Dimethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamideIsomer 2

(6RS)—N,N-dimethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide(25; 110 mg, 294 μmol) were separated by preparative HPLC (chiralmethod) to give the title compound (42 mg, 38%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.33 (1H), 2.46 (1H), 2.85 (3H), 2.95(1H), 3.03 (1H), 3.07 (3H), 3.66 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H),7.44 (1H), 7.46 (2H), 8.41 (2H), 11.96 (1H)

Example 61N-Methyl-4-oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamideIsomer 2

(6RS)—N-methyl-4-oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide(24; 20.5 mg, 51 μmol) were separated by preparative HPLC (chiralmethod) to give the title compound (9 mg, 44%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.81+0.86 (3H), 1.47+1.55 (2H),2.24-2.36 (1H), 2.47-2.59 (2H), 2.83+3.04 (3H), 2.89-3.08 (2H),3.19-3.36 (1H), 3.64 (1H), 6.60 (2H), 6.64 (1H), 7.05 (2H), 7.44 (1H),7.46 (2H), 8.42 (2H), 11.95 (1H)

Example 62(6RS)-3-(Phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture of[(6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (32-1; 150 mg, 365 μmol), sodium propane-2-thiolate(179 mg, 1.82 mmol) in DMA (5 mL) was stirred at 100° C. for 5 h. Themixture was concentrated and purified by preparative TLC (MeOH:DCM) togive the title compound (63 mg, 44%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.22 (6H), 2.30 (1H), 2.37 (1H), 2.46(1H), 2.62-2.72 (3H), 2.95 (1H), 3.13 (1H), 6.58 (2H), 6.63 (1H), 7.04(2H), 7.43 (1H), 7.47 (2H), 8.41 (2H), 11.94 (1H)

Example 63(6RS)-6-[(Ethylsulfanyl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture of[(6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (32-1; 150 mg, 365 μmol), sodium ethanethiolate (153mg, 1.82 mmol) in DMA (5 mL) was stirred at 100° C. for 5 h. The mixturewas concentrated and purified by preparative TLC (MeOH:DCM) to give thetitle compound (45 mg, 32%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.19 (3H), 2.29 (1H), 2.39 (1H), 2.45(1H), 2.54 (2H), 2.60-2.72 (3H), 3.13 (1H), 6.58 (2H), 6.63 (1H), 7.04(2H), 7.43 (1H), 7.46 (2H), 8.41 (2H), 11.94 (1H)

Example 644-Fluoro-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylbenzenesulfonamide

A mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 30 mg, 90 μmol), 4-fluorobenzenesulfonyl chloride (35 mg, 181 μmol)in pyridine (1 mL) was stirred at RT for 16 h. The mixture wasconcentrated and purified by preparative TLC (MeOH:DCM) to give thetitle compound (26 mg, 56%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.20 (1H), 2.28-2.35 (2H), 2.64 (1H),2.86 (2H), 2.99 (1H), 6.56 (2H), 6.63 (1H), 7.04 (2H), 7.42-7.49 (5H),7.85-7.90 (3H), 8.41 (2H), 11.94 (1H)

Example 65 2-Methoxyethyl[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamate

A mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 30 mg, 90 μmol), 2-methoxyethyl carbonochloridate (21 μL, 181 μmol)in pyridine (1 mL) was stirred at RT for 16 h. The mixture wasconcentrated and purified by preparative TLC (MeOH:DCM) to give thetitle compound (24 mg, 57%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.22 (1H), 2.27-2.37 (2H), 2.62 (1H),2.94 (1H), 3.10 (2H), 3.26 (3H), 3.50 (2H), 4.08 (2H), 6.57 (2H), 6.63(1H), 7.04 (2H), 7.41-7.49 (4H), 8.41 (2H), 11.93 (1H)

Example 66 2-Fluoroethyl[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamate

A mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 30 mg, 90 μmol), 2-fluoroethyl carbonochloridate (17 μL, 181 μmol)in pyridine (1 mL) was stirred at RT for 16 h. The mixture wasconcentrated and purified by preparative TLC (MeOH:DCM) to give thetitle compound (23 mg, 57%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.23 (1H), 2.28-2.39 (2H), 2.63 (1H),2.95 (1H), 3.12 (2H), 4.16 (1H), 4.26 (1H), 4.54 (1H), 4.66 (1H), 6.57(2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.47 (2H), 7.53 (1H), 8.41 (2H),11.94 (1H)

Example 67(6RS)-6-[(1,3-Benzothiazol-2-ylsulfanyl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture of[(6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (32-1; 150 mg, 365 μmol), sodium1,3-benzothiazole-2-thiolate (345 mg, 1.82 mmol) in DMA (5 mL) wasstirred at 100° C. for 5 h. The mixture was concentrated and purified bypreparative TLC (MeOH:DCM) to give the title compound (70 mg, 40%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.43 (1H), 2.53-2.55 (1H), 2.71 (1H),2.83 (1H), 3.16 (1H), 3.59 (2H), 6.58 (2H), 6.62 (1H), 7.03 (2H), 7.37(1H), 7.42-7.47 (4H), 7.83 (1H), 8.02 (1H), 8.40 (2H), 11.94 (1H)

Example 68(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid

A mixture of methyl(6RS)-2-[2-(acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate(50; 158 mg, 378 μmol), potassium hydroxide (1.51 mL, 4M in water), THF(1.5 mL) and MeOH (1.5 mL) was stirred at RT for 15 minutes.Hydrochloric acid (2.0 mL, 3M) was added and the mixture concentrated.The precipitate was washed with water and dried to give the titlecompound (106 mg, 66%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.07 (3H), 2.51-2.61 (2H), 3.07-3.23(3H), 6.55 (2H), 6.60 (1H), 7.01 (2H), 7.15 (1H), 7.37 (1H), 8.08 (1H),8.22 (1H), 10.36 (1H), 11.98 (1H), 12.62 (1H)

Example 69N-[(6RS)-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcyclopropanecarboxamide

A mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 30 mg, 90 μmol), cyclopropanecarbonyl chloride (16 μL, 181 μmol) inpyridine (1 mL) was stirred at RT for 16 h. The mixture was concentratedand purified by preparative TLC (MeOH:DCM) to give the title compound(27 mg, 71%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.62-0.73 (4H), 1.58 (1H), 2.24 (1H),2.30-2.40 (2H), 2.61 (1H), 2.94 (1H), 3.14 (1H), 3.23 (1H), 6.57 (2H),6.63 (1H), 7.04 (2H), 7.44 (1H), 7.47 (2H), 8.22 (1H), 8.41 (2H), 11.93(1H)

Example 702-Methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylpropanamide

A mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 30 mg, 90 μmol), 2-methylpropanoyl chloride (19 μL, 181 μmol) inpyridine (1 mL) was stirred at RT for 16 h. The mixture was concentratedand purified by preparative TLC (MeOH:DCM) to give the title compound(27 mg, 70%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03 (6H), 2.23 (1H), 2.28-2.43 (3H),2.60 (1H), 2.92 (1H), 3.09-3.22 (2H), 6.57 (2H), 6.63 (1H), 7.04 (2H),7.43 (1H), 7.46 (2H), 7.89 (1H), 8.41 (2H), 11.92 (1H)

Example 712-Methoxy-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylacetamide

A mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 30 mg, 90 μmol), methoxyacetyl chloride (17 μL, 181 μmol) inpyridine (1 mL) was stirred at RT for 16 h. The mixture was concentratedand purified by preparative TLC (MeOH:DCM) to give the title compound(30 mg, 77%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.22 (1H), 2.31 (1H), 2.41 (1H), 2.61(1H), 2.92 (1H), 3.15-3.28 (2H), 3.34 (3H), 3.84 (2H), 6.57 (2H), 6.63(1H), 7.04 (2H), 7.43 (1H), 7.46 (2H), 8.02 (1H), 8.41 (2H), 11.92 (1H)

Example 72N-[(6RS)-4-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcyclobutanecarboxamide

A mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 30 mg, 90 μmol), cyclobutanecarbonyl chloride (21 μL, 181 μmol) inpyridine (1 mL) was stirred at RT for 16 h. The mixture was concentratedand purified by preparative TLC (MeOH:DCM) to give the title compound(26 mg, 67%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.77 (1H), 1.89 (1H), 1.99-2.07 (2H),2.08-2.20 (2H), 2.24 (1H), 2.28-2.39 (2H), 2.59 (1H), 2.91 (1H), 3.03(1H), 3.11 (1H), 3.19 (1H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.43 (1H),7.46 (2H), 7.81 (1H), 8.41 (2H), 11.92 (1H)

Example 73N-[(6RS)-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylpropane-2-sulfonamide

A mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 50 mg, 150 μmol), propane-2-sulfonyl chloride (68 μL, 602 μmol) inpyridine (1.7 mL) was stirred at RT for 16 h. The mixture wasconcentrated and purified by preparative TLC (MeOH:DCM) to give thetitle compound (8 mg, 11%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.24 (6H), 2.22-2.44 (3H), 2.66 (1H),2.99-3.10 (3H), 3.20 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.21 (1H),7.44 (1H), 7.47 (2H), 8.41 (2H), 11.96 (1H)

Example 74N-(2-Hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamideIsomer 1

(6RS)—N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide(17; 120 mg, 297 μmol) were separated by preparative HPLC (chiralmethod) to give the title compound (36 mg, 30%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.30-2.38 (1H), 2.46-2.57 (1H),2.86+3.10 (3H), 2.92-3.07 (2H), 3.28-3.55 (4H), 3.64+3.72 (1H),4.69+4.86 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.42-7.48 (3H), 8.41(2H), 11.96 (1H)

Example 75N-(2-Hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamideIsomer 2

(6RS)—N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide(17; 120 mg, 297 μmol) were separated by preparative HPLC (chiralmethod) to give the title compound (30 mg, 24%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.30-2.38 (1H), 2.46-2.57 (1H),2.86+3.10 (3H), 2.92-3.07 (2H), 3.28-3.55 (4H), 3.64+3.72 (1H),4.69+4.86 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.42-7.48 (3H), 8.41(2H), 11.96 (1H)

Example 76(6RS)-2-(3-Fluoropyridin-4-yl)-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising(6RS)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (52; 70 mg, 192 μmol), DMF (2 mL), DIPEA (100 μL, 575 μmol),N-methylmethanamine (287 μL, 2M in THF) and T3P (173 μL, 50% in DMF) wasstirred at RT for 16 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (53 mg, 70%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.35 (1H), 2.52 (1H), 2.85 (3H),2.94-3.03 (2H), 3.07 (3H), 3.67 (1H), 6.59 (2H), 6.60 (1H), 6.99 (2H),7.40 (1H), 7.54 (1H), 8.24 (1H), 8.50 (1H), 11.68 (1H)

Example 77(6RS)-2-(3-Methoxypyridin-4-yl)-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising(6RS)-2-(3-methoxypyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (49; 70 mg, 185 μmol), DMF (2 mL), DIPEA (97 μL, 556 μmol),N-methylmethanamine (287 μL, 2M in THF) and T3P (167 μL, 50% in DMF) wasstirred at RT for 16 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (47 mg, 63%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.32 (1H), 2.52 (1H), 2.85 (3H),2.96-3.01 (2H), 3.07 (3H), 3.65 (1H), 3.89 (3H), 6.54 (2H), 6.58 (1H),6.98 (2H), 7.30 (1H), 7.41 (1H), 8.01 (1H), 8.34 (1H), 11.34 (1H)

Example 78(6RS)-2-(3-Fluoropyridin-4-yl)-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising(6RS)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (52; 70 mg, 192 μmol), DMF (2 mL), DIPEA (100 μL, 575 μmol),2-(methylamino)ethanol (46 μL, 575 μmol) and T3P (173 μL, 50% in DMF)was stirred at RT for 16 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (41 mg, 48%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.35 (1H), 2.54 (1H), 2.86+3.11 (3H),2.95-3.03 (2H), 3.29-3.55 (4H), 3.64+3.72 (1H), 4.68+4.86 (1H), 6.57(2H), 6.60 (1H), 6.99 (2H), 7.40 (1H), 7.54 (1H), 8.25 (1H), 8.50 (1H),11.68 (1H)

Example 79(6RS)—N-(2-Hydroxyethyl)-2-(3-methoxypyridin-4-yl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising(6RS)-2-(3-methoxypyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (49; 70 mg, 185 μmol), DMF (2 mL), DIPEA (97 μL, 556 μmol),2-(methylamino)ethanol (45 μL, 556 μmol) and T3P (167 μL, 50% in DMF)was stirred at RT for 16 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (54 mg, 67%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.29-2.36 (1H), 2.54 (1H), 2.86+3.11(3H), 2.95-3.03 (2H), 3.36-3.55 (4H), 3.62+3.71 (1H), 3.88+3.89 (3H),4.68+4.85 (1H), 6.54 (2H), 6.58 (1H), 6.98 (2H), 7.30 (1H), 7.40+7.41(1H), 8.01 (1H), 8.34 (1H), 11.34 (1H)

Example 80(6RS)-3-(Phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture comprising(6RS)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(62; 130 mg, 332 μmol), mCPBA (70 mg, 75%) and DMA (10 mL) was stirredat RT. After 4 h a second portion mCPBA (35 mg, 75%) was added and after4 h a third portion mCPBA (35 mg, 75%). The mixture was stirred at RTfor 16 h, Et₃N (200 μL) was added, the mixture concentrated and purifiedby preparative HPLC (basic method) to give the title compound (93 mg,63%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27 (6H), 2.42 (1H), 2.53-2.59 (2H),2.79-2.95 (2H), 3.24-3.32 (3H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.44(1H), 7.48 (2H), 8.42 (2H), 12.01 (1H)

Example 81(6RS)-6-[(Ethylsulfonyl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture comprising(6RS)-6-[(ethylsulfanyl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(63; 128 mg, 339 μmol), mCPBA (72 mg, 75%) and DMA (10 mL) was stirredat RT. After 4 h a second portion mCPBA (36 mg, 75%) was added and after4 h a third portion mCPBA (36 mg, 75%). The mixture was stirred at RTfor 16 h, Et₃N (200 μL) was added, the mixture concentrated and purifiedby preparative HPLC (basic method) to give the title compound (82 mg,56%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.24 (3H), 2.40 (1H), 2.53 (1H),2.79-2.91 (2H), 3.16 (2H), 3.24-3.35 (3H), 6.58 (2H), 6.63 (1H), 7.04(2H), 7.44 (1H), 7.47 (2H), 8.41 (2H), 12.01 (1H)

Example 823-Methoxy-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylpropanamide

A mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 30 mg, 90 μmol), 3-methoxypropanoyl chloride (22 mg, 181 μmol) inpyridine (1 mL) was stirred at RT for 16 h. MeOH was added, the mixtureconcentrated and purified by crystallization from MeOH to give the titlecompound (13 mg, 34%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.27-2.42 (5H), 2.68 (1H), 3.00 (1H),3.13-3.25 (2H), 3.22 (3H), 3.54 (2H), 6.70 (2H), 6.76 (1H), 7.12 (2H),7.79 (2H), 8.03-8.10 (2H), 8.59 (2H), 12.63 (1H)

Example 83(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising(6RS)-2-[2-(acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (68; 50 mg, 123 μmol), DMF (2 mL), DIPEA (65 μL, 371 μmol),N-methylmethanamine (185 μL, 2M in THF) and T3P (111 μL, 50% in DMF) wasstirred at RT for 16 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (28 mg, 52%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.07 (3H), 2.31 (1H), 2.49 (1H), 2.85(3H), 2.94-3.01 (2H), 3.06 (3H), 3.64 (1H), 6.57 (2H), 6.61 (1H), 7.02(2H), 7.15 (1H), 7.36 (1H), 8.08 (1H), 8.23 (1H), 10.35 (1H), 11.95 (1H)

Example 84(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising(6RS)-2-[2-(acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (68; 50 mg, 123 μmol), DMF (2 mL), DIPEA (65 μL, 371 μmol),2-(methylamino)ethanol (30 μL, 371 μmol) and T3P (111 μL, 50% in DMF)was stirred at RT for 16 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (33 mg, 55%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.07 (3H), 2.28-2.36 (1H), 2.53-2.59(1H), 2.85+3.10 (3H), 2.93-3.03 (2H), 3.29-3.54 (4H), 3.62+3.69 (1H),4.69+4.85 (1H), 6.57 (2H), 6.61 (1H), 7.02 (2H), 7.15 (1H), 7.35+7.36(1H), 8.08 (1H), 8.23 (1H), 10.35 (1H), 11.96 (1H)

Example 85 Methyl4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylateIsomer 1

Methyl(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate(8; 213 mg, 589 μmol) were separated by preparative HPLC (chiral method)to give the title compound (80 mg, 38%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.56-2.62 (2H), 3.09-3.21 (2H), 3.37(1H), 3.64 (3H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.44-7.49 (3H), 8.42(2H), 12.00 (1H)

Example 86 Methyl4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylateIsomer 2

Methyl(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate(8; 213 mg, 589 μmol) were separated by preparative HPLC (chiral method)to give the title compound (85 mg, 38%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.56-2.62 (2H), 3.09-3.21 (2H), 3.37(1H), 3.64 (3H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.44-7.49 (3H), 8.42(2H), 12.00 (1H)

Example 87(6RS)-2-(2-Aminopyridin-4-yl)-6-(hydroxymethyl)-3-(phenylamino)-1,5,6,7-tetrahydro-4H-indol-4-one87-2:(4RS)-2-{[(2-Aminopyridin-4-yl)methyl]amino}-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-oxo-N-phenylcyclohex-1-ene-1-carbothioamide

A solution of(4RS)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-hydroxy-6-oxo-N-phenylcyclohex-1-ene-1-carbothioamide(1-3; 33.9 g, 65.7 mmol) and 4-(aminomethyl)pyridin-2-amine (16.2 g, 131mmol) in DMA (250 mL) was heated at 120° C. for 2 h. The mixture wasconcentrated and purified by Biotage (SNAP silica 750 g, EtOH:DCM) togive the title compound (24.8 g, 60%).

87-1:(6RS)-2-(2-Aminopyridin-4-yl)-3-anilino-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture of(4RS)-2-{[(2-Aminopyridin-4-yl)methyl]amino}-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-oxo-N-phenylcyclohex-1-ene-1-carbothioamide(87-2; 16.3 g, 26.3 mmol), hydrogen peroxide (30% in water, 10.7 mL, 105mmol) in MeOH (500 mL) was heated at 50° C. for 16 h. The mixture wasconcentrated and purified by Biotage (SNAP silica 375 g, MeOH:DCM) togive the title compound (8.95 g, 58%).

(6RS)-2-(2-Aminopyridin-4-yl)-6-(hydroxymethyl)-3-(phenylamino)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture of(6RS)-2-(2-Aminopyridin-4-yl)-3-anilino-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-1,5,6,7-tetrahydro-4H-indol-4-one(87-1; 3.0 g, 5.11 mmol) and TBAF (6.1 mL, 1M in THF) in THF (80 mL) wasstirred at 50° C. for 2 h. EtOAc (1 L) was added, the mixture washedwith sodium hydroxide (2.5% in water), brine and dried over sodiumsulfate. After filtration and removal of the solvent the residue waspurified by Biotage (SNAP silica 110 g, MeOH:DCM) to give the titlecompound (1.17 g, 62%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.16-2.34 (3H), 2.62 (1H), 2.93 (1H),3.43 (2H), 4.74 (1H), 5.73 (2H), 6.53-6.62 (4H), 6.69 (1H), 7.02 (2H),7.23 (1H), 7.75 (1H), 11.69 (1H)

Example 884-Fluoro-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylbenzamide

A solution of 4-fluorobenzoic acid (34 mg, 241 μmol) and HATU (92 mg,241 μmol) in DMA (1 mL) was added to a mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 40 mg, 120 μmol) and DIPEA (42 μL, 241 μmol) in DMA (1 mL) and thereaction was stirred at 50° C. for 16 h. The mixture was concentratedand purified by preparative HPLC (basic method) to give the titlecompound (33 mg, 58%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.28-2.41 (2H), 2.53-2.58 (1H), 2.69(1H), 2.99 (1H), 3.31-3.46 (2H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.32(2H), 7.44 (1H), 7.46 (2H), 7.96 (2H), 8.40 (2H), 8.66 (1H), 11.92 (1H)

Example 89 tert-Butyl[(2S)-1-oxo-1-([(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylamino)propan-2-yl]carbamate

A solution of N-(tert-butoxycarbonyl)-L-alanine (129 mg, 680 μmol) andHATU (258 mg, 680 μmol) in DMA (3 mL) was added to a mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 113 mg, 340 μmol) and DIPEA (118 μL, 680 μmol) in DMA (3 mL) andthe reaction was stirred at RT for 16 h. The mixture was concentratedand purified by Biotage (SNAP silica 28 g, MeOH:DCM) to give the titlecompound (56 mg, 33%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20 (3H), 1.36 (9H), 2.19-2.40 (3H),2.61 (1H), 2.90 (1H), 3.09-3.29 (2H), 3.94 (1H), 6.57 (2H), 6.63 (1H),6.92 (1H), 7.04 (2H), 7.43 (1H), 7.46 (2H), 7.93 (1H), 8.41 (2H), 11.93(1H)

Example 90 tert-Butyl(2S)-2-([(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamoyl)pyrrolidine-1-carboxylate

A solution of 1-(tert-butoxycarbonyl)-L-proline (97 mg, 451 μmol) andHATU (172 mg, 451 μmol) in DMA (2 mL) was added to a mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 75 mg, 226 μmol) and DIPEA (79 μL, 451 μmol) in DMA (2 mL) and thereaction was stirred at RT for 16 h. The mixture was concentrated andpurified by Biotage (SNAP silica 28 g, MeOH:DCM) to give the titlecompound (85 mg, 71%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31+1.38 (9H), 1.73-1.88 (3H), 2.12(1H), 2.24 (1H), 2.25-2.42 (2H), 2.63 (1H), 2.92 (1H), 3.13 (1H),3.20-3.31 (2H), 3.40 (1H), 4.06 (1H), 6.57 (2H), 6.63 (1H), 7.04 (2H),7.42 (1H), 7.47 (2H), 7.96+8.05 (1H), 8.41 (2H), 11.91 (1H)

Example 91(2S)-2-Hydroxy-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylpropanamide

A solution of (2S)-2-hydroxypropanoic acid (22 mg, 241 μmol) and HATU(92 mg, 241 μmol) in DMA (1 mL) was added to a mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 40 mg, 120 μmol) and DIPEA (42 μL, 241 μmol) in DMA (1 mL) and thereaction was stirred at 50° C. for 16 h. The mixture was concentratedand purified preparative HPLC (basic method) to give the title compound(29 mg, 56%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.24 (3H), 2.22 (1H), 2.30 (1H), 2.40(1H), 2.61 (1H), 2.91 (1H), 3.13-3.27 (2H), 4.00 (1H), 5.51 (1H), 6.57(2H), 6.63 (1H), 7.04 (2H), 7.43 (1H), 7.46 (2H), 7.91 (1H), 8.40 (2H),11.93 (1H)

Example 92N-[(6RS)-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-1,3-thiazole-2-carboxamide

A solution of 1,3-thiazole-2-carboxylic acid (31 mg, 241 μmol) and HATU(92 mg, 241 μmol) in DMA (1 mL) was added to a mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 40 mg, 120 μmol) and DIPEA (42 μL, 241 μmol) in DMA (1 mL) and thereaction was stirred at 50° C. for 16 h. The mixture was concentratedand purified preparative HPLC (basic method) to give the title compound(22 mg, 39%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.26-2.38 (2H), 2.55 (1H), 2.68 (1H),2.97 (1H), 3.31-3.47 (2H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.42-7.47(3H), 8.04 (1H), 8.07 (1H), 8.40 (2H), 9.09 (1H), 11.91 (1H)

Example 931-Methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-1H-pyrrole-2-carboxamide

A solution of 1-methyl-1H-pyrrole-2-carboxylic acid (30 mg, 241 μmol)and HATU (92 mg, 241 μmol) in DMA (1 mL) was added to a mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 40 mg, 120 μmol) and DIPEA (42 μL, 241 μmol) in DMA (1 mL) and thereaction was stirred at RT for 16 h. The mixture was concentrated andpurified preparative HPLC (basic method) to give the title compound (6mg, 11%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.24-2.39 (2H), 2.42-2.54 (1H), 2.66(1H), 2.98 (1H), 3.22-3.36 (2H), 3.84 (3H), 6.02 (1H), 6.57 (2H), 6.63(1H), 6.81 (1H), 6.90 (1H), 7.04 (2H), 7.43 (1H), 7.46 (2H), 8.12 (1H),8.40 (2H), 11.92 (1H)

Example 94N-4-[(6RS)-6-(Hydroxymethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide94-1:N-{4-[(6RS)-3-Anilino-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide

A mixture of(6RS)-2-(2-Aminopyridin-4-yl)-3-anilino-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-1,5,6,7-tetrahydro-4H-indol-4-one(87-1; 2.34 g, 3.99 mmol), acetyl chloride (425 μL, 5.98 mmol) in THF(100 mL) and pyridine (2.78 mL) was stirred at RT for 1 h. MeOH wasadded, the mixture concentrated and purified by Biotage (SNAP silica 50g, MeOH:DCM) to give the title compound (2.46 g, 98%).

N-4-[(6RS)-6-(Hydroxymethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide

A mixture ofN-{4-[(6RS)-3-anilino-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide(94-1; 2.45 g, 3.90 mmol) and TBAF (4.68 mL, 1M in THF) in THF (65 mL)was stirred at RT for 16 h. EtOAc was added, the mixture washed withsodium hydroxide (2.5% in water), brine and dried over sodium sulfate.After filtration and removal of the solvent the residue was purified bycrystallization from MeOH/DCM and Biotage (SNAP silica 25 g, MeOH:DCM)of the mother liquor to give the title compound (1.17 g, 77%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.07 (3H), 2.19-2.35 (3H), 2.65 (1H),2.96 (1H), 3.39-3.48 (2H), 4.75 (1H), 6.56 (2H), 6.60 (1H), 7.01 (2H),7.15 (1H), 7.36 (1H), 8.08 (1H), 8.22 (1H), 10.34 (1H), 11.91 (1H)

Example 95N-[(6RS)-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyltetrahydro-2H-pyran-4-carboxamide

A mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 30 mg, 90 μmol), tetrahydro-2H-pyran-4-carbonyl chloride (27 mg,181 μmol) in pyridine (1 mL) was stirred at RT for 16 h. The mixture wasconcentrated and purified by preparative TLC (MeOH:DCM) to give thetitle compound (19 mg, 45%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.57-1.65 (4H), 2.20-2.43 (4H), 2.60(1H), 2.92 (1H), 3.16 (2H), 3.26-3.35 (2H), 3.87 (2H), 6.57 (2H), 6.63(1H), 7.04 (2H), 7.43 (1H), 7.47 (2H), 7.95 (1H), 8.40 (2H), 11.98 (1H)

Example 96N-[(6RS)-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylfuran-2-carboxamide

A mixture of(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(36; 30 mg, 90 μmol), 2-furoyl chloride (18 μL, 181 μmol) in pyridine (1mL) was stirred at RT for 16 h. The mixture was concentrated andpurified by preparative TLC (MeOH:DCM) to give the title compound (16mg, 40%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.28 (1H), 2.36 (1H), 2.45-2.54 (1H),2.66 (1H), 2.97 (1H), 3.26-3.42 (2H), 6.57 (2H), 6.63 (1H), 6.64 (1H),7.04 (2H), 7.13 (1H), 7.44 (1H), 7.45 (2H), 7.86 (1H), 8.40 (2H), 8.55(1H), 11.91 (1H)

Example 97(6RS)—N-(2-Hydroxy-2-methylpropyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (1.5 mL), DIPEA (89 μL, 518 μmol),2-methyl-1-(methylamino)propan-2-ol (61 μL, 518 μmol) and T3P (156 μL,50% in DMF) was stirred at RT for 1 h. The mixture was filtered andpurified by preparative HPLC (basic method) to give the title compound(49 mg, 66%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.04+1.11 (6H), 2.28+2.38 (1H),2.47-2.57 (1H), 2.88-3.08 (2H), 2.94+3.18 (3H), 3.23-3.39 (2H),3.68+3.83 (1H), 4.51+4.60 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.44(1H), 7.46 (2H), 8.41 (2H), 11.92+11.95 (1H)

Example 98(6RS)—N-[(2S)-2-Hydroxypropyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (0.95 mL), DIPEA (89 μL, 518 μmol),(2S)-1-aminopropan-2-ol (41 μL, 518 μmol) and T3P (156 μL, 50% in DMF)was stirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (42 mg, 57%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02 (3H), 2.39 (1H), 2.55 (1H),2.95-3.18 (5H), 3.65 (1H), 4.69 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H),7.44 (1H), 7.46 (2H), 7.99 (1H), 8.42 (2H), 11.96 (1H)

Example 99(6RS)—N-(1-Hydroxy-2-methylpropan-2-yl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (89 μL, 518 μmol),2-amino-2-methylpropan-1-ol (49 μL, 518 μmol) and T3P (156 μL, 50% inDMF) was stirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (26 mg, 36%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.19 (6H), 2.36 (1H), 2.47-2.55 (1H),2.91-3.15 (3H), 3.41 (2H), 4.81 (1H), 6.57 (2H), 6.63 (1H), 7.04 (2H),7.42-7.49 (4H), 8.41 (2H), 11.95 (1H)

Example 100(6RS)—N-(2,2-Dimethylpropyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (89 μL, 518 μmol),2,2-dimethylpropan-1-amine (61 μL, 518 μmol) and T3P (156 μL, 50% inDMF) was stirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (48 mg, 60%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.84 (9H), 2.37 (1H), 2.57 (1H),2.89-3.09 (4H), 3.17 (1H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H),7.46 (2H), 7.90 (1H), 8.41 (2H), 11.97 (1H)

Example 101(6RS)—N-(2-Methylpropyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (89 μL, 518 μmol),2-methylpropan-1-amine (51 μL, 518 μmol) and T3P (156 μL, 50% in DMF)was stirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (48 mg, 69%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.85 (6H), 1.69 (1H), 2.38 (1H), 2.56(1H), 2.86-3.05 (4H), 3.10 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.44(1H), 7.47 (2H), 7.99 (1H), 8.41 (2H), 11.98 (1H)

Example 102(6RS)—N-Methyl-N-(2-methylpropyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (89 μL, 518 μmol),N,2-dimethylpropan-1-amine (62 μL, 518 μmol) and T3P (156 μL, 50% inDMF) was stirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (32 mg, 44%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80-0.89 (6H), 1.90 (1H), 2.25+2.35(1H), 2.46-2.58 (1H), 2.83+3.05 (3H), 2.92-3.25 (4H), 3.66 (1H),6.58-6.66 (3H), 7.05 (2H), 7.43-7.47 (3H), 8.41 (2H), 11.95 (1H)

Example 103(6RS)—N-[2-(Dimethylamino)ethyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (89 μL, 518 μmol),N,N-dimethylethane-1,2-diamine (57 μL, 518 μmol) and T3P (156 μL, 50% inDMF) was stirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (27 mg, 36%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.15 (6H), 2.29 (2H), 2.37 (1H), 2.54(1H), 2.94-3.21 (5H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.46(2H), 7.95 (1H), 8.41 (2H), 11.95 (1H)

Example 104(6RS)—N-[2-(Dimethylamino)ethyl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (89 μL, 518 μmol),N,N,N′-trimethylethane-1,2-diamine (67 μL, 518 μmol) and T3P (156 μL,50% in DMF) was stirred at RT for 1 h. The mixture was filtered andpurified by preparative HPLC (basic method) to give the title compound(33 mg, 42%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.15+2.17 (6H), 2.28-2.42 (3H),2.46-2.55 (1H), 2.86+3.07 (3H), 2.92-3.05 (2H), 3.36-3.51 (2H), 3.63(1H), 6.59 (2H), 6.64 (1H), 7.04 (2H), 7.43-7.47 (3H), 8.41 (2H), 11.95(1H)

Example 105(6RS)—N-Methyl-N-[2-(methylamino)ethyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (89 μL, 518 μmol),N,N′-dimethylethane-1,2-diamine (56 μL, 518 μmol) and T3P (156 μL, 50%in DMF) was stirred at RT for 1 h. The mixture was filtered and purifiedby preparative HPLC (basic method) to give the title compound (15 mg,19%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.27+2.28 (3H), 2.29-2.37 (1H),2.48-2.55 (1H), 2.60 (2H), 2.85+3.07 (3H), 2.92-3.03 (2H), 3.32-3.45(2H), 3.64 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.43 (1H), 7.46 (2H),8.41 (2H), 11.96 (1H)

Example 106(6RS)—N-(2,2-Difluoroethyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (89 μL, 518 μmol),2,2-difluoroethanamine (37 μL, 518 μmol) and T3P (156 μL, 50% in DMF)was stirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (36 mg, 46%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.41 (1H), 2.56 (1H), 3.03 (2H), 3.17(1H), 3.52 (2H), 6.03 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.45 (1H),7.46 (2H), 8.42 (2H), 8.44 (1H), 11.97 (1H)

Example 107(6RS)—N-Methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-N-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (89 μL, 518 μmol),2,2,2-trifluoro-N-methylethanamine (59 mg, 518 μmol) and T3P (156 μL,50% in DMF) was stirred at RT for 1 h. The mixture was filtered andpurified by preparative HPLC (basic method) to give the title compound(21 mg, 26%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.26+2.36 (1H), 2.47-2.56 (1H),2.88-3.07 (2H), 2.98+3.20 (3H), 3.76 (1H), 4.21+4.49 (2H), 6.59 (2H),6.64 (1H), 7.05 (2H), 7.44 (1H), 7.46 (2H), 8.42 (2H), 11.97 (1H)

Example 108(6RS)-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-N-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (89 μL, 518 μmol),3,3,3-trifluoropropan-1-amine (51 μL, 518 μmol) and T3P (156 μL, 50% inDMF) was stirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (38 mg, 47%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.35-2.58 (5H), 2.96-3.12 (3H), 3.31(1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.46 (2H), 8.26 (1H),8.41 (2H), 11.97 (1H)

Example 109(6RS)—N-(2,2-Difluoroethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (89 μL, 518 μmol),2,2-difluoro-N-methylethanamine (61 μL, 518 μmol) and T3P (156 μL, 50%in DMF) was stirred at RT for 1 h. The mixture was filtered and purifiedby preparative HPLC (basic method) to give the title compound (31 mg,42%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.29+2.36 (1H), 2.44-2.57 (1H),2.89-3.07 (2H), 2.93+3.16 (3H), 3.64-3.81+3.96 (3H), 6.12 (1H), 6.59(2H), 6.64 (1H), 7.05 (2H), 7.43 (1H), 7.46 (2H), 8.42 (2H), 11.97 (1H)

Example 110(6RS)—N-tert-Butyl-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (89 μL, 518 μmol),N,2-dimethylpropan-2-amine (62 μL, 518 μmol) and T3P (156 μL, 50% inDMF) was stirred at RT for 1 day. The mixture was filtered and purifiedby preparative HPLC (basic method) to give the title compound (16 mg,20%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35 (9H), 2.32 (1H), 2.48 (1H),2.89-3.05 (2H), 2.95 (3H), 3.64 (1H), 6.59 (2H), 6.63 (1H), 7.04 (2H),7.43 (1H), 7.45 (2H), 8.41 (2H), 11.92 (1H)

Example 111(6RS)—N-[(1-Hydroxycyclopropyl)methyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (89 μL, 518 μmol),1-(aminomethyl)cyclopropanol (38 μL, 518 μmol) and T3P (156 μL, 50% inDMF) was stirred at RT for 1 day. The mixture was filtered and purifiedby preparative HPLC (basic method) to give the title compound (25 mg,31%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.48 (2H), 0.52 (2H), 2.38 (1H), 2.54(1H), 2.94-3.09 (2H), 3.14 (1H), 3.24 (2H), 5.34 (1H), 6.57 (2H), 6.62(1H), 7.03 (2H), 7.44 (1H), 7.45 (2H), 8.03 (1H), 8.41 (2H), 11.95 (1H)

Example 112(6RS)—N-(2-Hydroxy-2-methylpropyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (89 μL, 518 μmol),2,2-dimethylpropan-1-amine (61 μL, 518 μmol) and T3P (156 μL, 50% inDMF) was stirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (41 mg, 72%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.05 (3H), 1.06 (3H), 2.38 (1H), 2.56(1H), 2.96-3.11 (4H), 3.20 (1H), 4.47 (1H), 6.58 (2H), 6.63 (1H), 7.04(2H), 7.44 (1H), 7.46 (2H), 7.90 (1H), 8.41 (2H), 11.96 (1H)

Example 113(6RS)-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-N-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (89 μL, 518 μmol),2,2-dimethylpropan-1-amine (61 μL, 518 μmol) and T3P (156 μL, 50% inDMF) was stirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (30 mg, 36%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.41 (1H), 2.56 (1H), 3.04 (2H), 3.20(1H), 3.94 (2H), 6.57 (2H), 6.62 (1H), 7.03 (2H), 7.44 (1H), 7.46 (2H),8.41 (2H), 8.70 (1H), 11.97 (1H)

Example 114(6RS)—N-Methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-N-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (89 μL, 518 μmol),3,3,3-trifluoro-N-methylpropan-1-amine hydrochloride (85 mg, 518 μmol)and T3P (156 μL, 50% in DMF) was stirred at RT for 1 h. The mixture wasfiltered and purified by preparative HPLC (basic method) to give thetitle compound (48 mg, 79%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.31 (1H), 2.41-2.56 (3H), 2.85+3.08(3H), 2.91-3.04 (2H), 3.46-3.68 (3H), 6.59 (2H), 6.63 (1H), 7.04 (2H),7.43 (1H), 7.46 (2H), 8.41 (2H), 11.96 (1H)

Example 115(6RS)—N-[(2R)-2-Hydroxypropyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (89 μL, 518 μmol),2(2R)-1-aminopropan-2-ol (41 μL, 518 μmol) and T3P (156 μL, 50% in DMF)was stirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (42 mg, 57%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02 (3H), 2.39 (1H), 2.55 (1H),2.95-3.08 (4H), 3.14 (1H), 3.65 (1H), 4.71 (1H), 6.58 (2H), 6.63 (1H),7.04 (2H), 7.44 (1H), 7.46 (2H), 7.99 (1H), 8.42 (2H), 11.96 (1H)

Example 1164-Oxo-3-(phenylamino)-2-(pyridin-4-y0-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid Isomer 1

4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 50 mg, 144 μmol) were separated by preparative HPLC (chiralmethod) to give the title compound (15 mg, 29%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.60 (2H), 3.17 (2H), 3.27 (1H), 6.63(2H), 6.69 (1H), 7.08 (2H), 7.63 (2H), 7.77 (1H), 8.50 (2H), 12.39 (1H),12.65 (1H)

Example 1174-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid Isomer 2

4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 50 mg, 144 μmol) were separated by preparative HPLC (chiralmethod) to give the title compound (15 mg, 29%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.60 (2H), 3.17 (2H), 3.27 (1H), 6.63(2H), 6.69 (1H), 7.08 (2H), 7.63 (2H), 7.77 (1H), 8.50 (2H), 12.39 (1H),12.65 (1H)

Example 118(6RS)-6-[(4-Methylpiperazin-1-yl)carbonyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 50 mg, 144 μmol), DMF (1.5 mL), DIPEA (75 μL, 432 μmol),1-methylpiperazine (48 μL, 432 μmol) and T3P (130 μL, 50% in DMF) wasstirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (40 mg, 65%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.19 (3H), 2.22-2.36 (5H), 2.53 (1H),2.93-3.07 (2H), 3.41-3.58 (4H), 3.67 (1H), 6.59 (2H), 6.63 (1H), 7.04(2H), 7.43 (1H), 7.46 (2H), 8.41 (2H), 11.95 (1H)

Example 119(6RS)-6-[(3S)-3-Hydroxypyrrolidin-1-yl]carbonyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (90 μL, 518 μmol),(3S)-pyrrolidin-3-ol (42 μL, 518 μmol) and T3P (156 μL, 50% in DMF) wasstirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (44 mg, 61%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.71-1.99 (2H), 2.32-2.39 (1H),2.44-2.55 (2H), 2.92-3.09 (2H), 3.24-3.69 (4H), 4.26+4.32 (1H),4.94+5.03 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.44 (1H), 7.46 (2H),8.41 (2H), 11.97 (1H)

Example 120(6RS)-6-[(3R)-3-Hydroxypyrrolidin-1-yl]carbonyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (89 μL, 518 μmol),(3R)-pyrrolidin-3-ol (42 μL, 518 μmol) and T3P (156 μL, 50% in DMF) wasstirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (38 mg, 48%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.72-1.99 (2H), 2.32-2.39 (1H),2.42-2.55 (2H), 2.92-3.09 (2H), 3.26-3.68 (4H), 4.26+4.32 (1H),4.95+5.03 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.44 (1H), 7.46 (2H),8.41 (2H), 11.97 (1H)

Example 121(6RS)-6-[(3-Hydroxyazetidin-1-yl)carbonyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 50 mg, 144 μmol), DMF (1.5 mL), DIPEA (150 μL, 863 μmol),azetidin-3-ol hydrochloride (47 mg, 432 μmol) and T3P (130 μL, 50% inDMF) was stirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (54 mg, 58%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.31 (1H), 2.45 (1H), 2.89-3.02 (2H),3.23 (1H), 3.60 (1H), 3.93 (1H), 4.06 (1H), 4.39 (1H), 4.46 (1H), 5.75(1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.43 (1H), 7.46 (2H), 8.42 (2H),11.97 (1H)

Example 122(6RS)—N,N-Diethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 50 mg, 144 μmol), DMF (1.5 mL), DIPEA (75 μL, 432 μmol),N-ethylethanamine (46 μL, 432 μmol) and T3P (130 μL, 50% in DMF) wasstirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (37 mg, 61%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03 (3H), 1.13 (3H), 2.27 (1H), 2.56(1H), 2.92 (1H), 3.05 (1H), 3.24 (1H), 3.30-3.42 (3H), 3.55 (1H), 6.60(2H), 6.64 (1H), 7.05 (2H), 7.44 (1H), 7.46 (2H), 8.41 (2H), 11.95 (1H)

Example 123N-[(6RS)-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]acetamide

A mixture of4-[(6RS)-6-ammonio-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridiniumchloride (5; 40 mg, 102 μmol), acetyl chloride (15 μL, 204 μmol) inpyridine (2 mL) was stirred at RT for 16 h. The mixture was concentratedand purified by preparative HPLC (basic method) to give the titlecompound (11 mg, 27%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.82 (3H), 2.43 (1H), 2.53 (1H), 2.84(1H), 3.16 (1H), 4.30 (1H), 6.58-6.60 (2H), 6.64 (1H), 7.05 (2H), 7.47(1H), 7.48 (2H), 8.25 (1H), 8.43 (2H), 12.00 (1H)

Example 1242-Methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]propanamide

A mixture of4-[(6RS)-6-ammonio-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridiniumchloride (5; 40 mg, 102 μmol), 2-methylpropanoyl chloride (21 μL, 204μmol) in pyridine (2 mL) was stirred at RT for 16 h. The mixture wasconcentrated and purified by preparative HPLC (basic method) to give thetitle compound (9 mg, 23%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.99 (3H), 1.00 (3H), 2.37 (1H),2.44-2.53 (2H), 2.84 (1H), 3.15 (1H), 4.29 (1H), 6.59 (2H), 6.63 (1H),7.04 (2H), 7.46 (1H), 7.47 (2H), 8.11 (1H), 8.42 (2H), 11.96 (1H)

Example 1253-Methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide

A mixture of4-[(6RS)-6-ammonio-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridiniumchloride (5; 40 mg, 102 μmol), 3-methylbutanoyl chloride (25 μL, 204μmol) in pyridine (2 mL) was stirred at RT for 16 h. The mixture wasconcentrated and purified by preparative HPLC (basic method) to give thetitle compound (15 mg, 35%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.87 (6H), 1.91-2.00 (3H), 2.46 (1H),2.53 (1H), 2.86 (1H), 3.16 (1H), 4.32 (1H), 6.59 (2H), 6.63 (1H), 7.04(2H), 7.45 (1H), 7.46 (2H), 8.18 (1H), 8.42 (2H), 11.97 (1H)

Example 1263-Hydroxy-3-methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide

A mixture comprising4-[(6RS)-6-ammonio-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridiniumchloride (5; 40 mg, 102 μmol), DMF (1.5 mL), DIPEA (107 μL, 613 μmol),3-hydroxy-3-methylbutanoic acid (33 μL, 307 μmol) and T3P (184 μL, 50%in DMF) was stirred at RT for 2 h. The mixture was filtered and purifiedby preparative HPLC (basic method) to give the title compound (9 mg,20%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.14 (6H), 2.21 (2H), 2.45 (1H), 2.53(1H), 2.88 (1H), 3.17 (1H), 4.36 (1H), 4.73 (1H), 6.60 (2H), 6.63 (1H),7.04 (2H), 7.44 (1H), 7.46 (2H), 8.21 (1H), 8.42 (2H), 11.97 (1H)

Example 1272-Cyclopropyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]acetamide

A mixture comprising4-[(6RS)-6-ammonio-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridiniumchloride (5; 40 mg, 102 μmol), DMF (1.5 mL), DIPEA (107 μL, 613 μmol),cyclopropylacetic acid (29 μL, 307 μmol) and T3P (184 μL, 50% in DMF)was stirred at RT for 2 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (17 mg, 39%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.11 (2H), 0.42 (2H), 0.95 (1H), 1.99(2H), 2.44 (2H), 2.86 (1H), 3.16 (1H), 4.32 (1H), 6.60 (2H), 6.64 (1H),7.05 (2H), 7.44 (1H), 7.47 (2H), 8.10 (1H), 8.42 (2H), 11.96 (1H)

Example 128(3S)-3-Hydroxy-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide

A mixture comprising4-[(6RS)-6-ammonio-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridiniumchloride (5; 40 mg, 102 μmol), DMF (1.5 mL), DIPEA (107 μL, 613 μmol),(3S)-3-hydroxybutanoic acid (32 mg, 307 μmol) and T3P (184 μL, 50% inDMF) was stirred at RT for 2 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (18 mg, 39%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.25 (1H), 1.06 (3H), 2.11 (1H), 2.22(1H), 2.44 (1H), 2.85 (1H), 3.15 (1H), 3.60 (1H), 3.98 (1H), 4.32 (1H),6.59 (2H), 6.63 (1H), 7.05 (2H), 7.44 (1H), 7.46 (2H), 8.19 (1H), 8.42(2H), 11.96 (1H)

Example 1293-Hydroxy-2,2-dimethyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]propanamide

A mixture comprising4-[(6RS)-6-ammonio-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridiniumchloride (5; 40 mg, 102 μmol), DMF (1.5 mL), DIPEA (107 μL, 613 μmol),3-hydroxy-2,2-dimethylpropanoic acid (36 mg, 307 μmol) and T3P (184 μL,50% in DMF) was stirred at RT for 2 h. The mixture was filtered andpurified by preparative HPLC (basic method) to give the title compound(11 mg, 24%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.04 (6H), 2.41 (1H), 2.54 (1H), 2.90(1H), 3.09 (1H), 3.37 (2H), 4.34 (1H), 4.90 (1H), 6.59 (2H), 6.63 (1H),7.04 (2H), 7.44 (1H), 7.47 (2H), 7.65 (1H), 8.42 (2H), 11.95 (1H)

Example 130N-[(2S)-1-Hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamideIsomer 1

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (90 μL, 518 μmol),(2S)-2-aminopropan-1-ol (40 μL, 518 μmol) and T3P (156 μL, 50% in DMF)was stirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (28 mg, 36%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.04 (3H), 2.38 (1H), 2.53 (1H),2.93-3.12 (3H), 3.23 (1H), 3.32-3.37 (1H), 3.78 (1H), 4.71 (1H), 6.58(2H), 6.63 (1H), 7.04 (2H), 7.45 (1H), 7.46 (2H), 7.80 (1H), 8.41 (2H),11.96 (1H)

Example 131N-[(2S)-1-Hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamideIsomer 2

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (90 μL, 518 μmol),(2S)-2-aminopropan-1-ol (40 μL, 518 μmol) and T3P (156 μL, 50% in DMF)was stirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (29 mg, 39%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03 (3H), 2.37 (1H), 2.54 (1H),2.94-3.12 (3H), 3.25 (1H), 3.37 (1H), 3.77 (1H), 4.71 (1H), 6.58 (2H),6.63 (1H), 7.04 (2H), 7.45 (1H), 7.46 (2H), 7.79 (1H), 8.41 (2H), 11.95(1H)

Example 132N-[(2R)-1-Hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyriclin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamideIsomer 1

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (90 μL, 518 μmol),(2R)-2-aminopropan-1-ol (40 μL, 518 μmol) and T3P (156 μL, 50% in DMF)was stirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (26 mg, 35%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.04 (3H), 2.38 (1H), 2.53 (1H),2.93-3.12 (3H), 3.23 (1H), 3.34 (1H), 3.78 (1H), 4.71 (1H), 6.58 (2H),6.63 (1H), 7.04 (2H), 7.45 (1H), 7.46 (2H), 7.80 (1H), 8.41 (2H), 11.95(1H)

Example 133(3R)-3-Hydroxy-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-y0-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide

A mixture comprising4-[(6RS)-6-ammonio-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridiniumchloride (5; 40 mg, 102 μmol), DMF (1.5 mL), DIPEA (107 μL, 613 μmol),(3R)-3-hydroxybutanoic acid (32 mg, 307 μmol) and T3P (184 μL, 50% inDMF) was stirred at RT for 2 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (14 mg, 30%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.06 (3H), 2.11 (1H), 2.22 (1H),2.40-2.55 (2H), 2.85 (1H), 3.15 (1H), 3.97 (1H), 4.32 (1H), 4.64 (1H),6.59 (2H), 6.63 (1H), 7.05 (2H), 7.44 (1H), 7.46 (2H), 8.19 (1H), 8.42(2H), 11.96 (1H)

Example 134N-[(2R)-1-Hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamideIsomer 2

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (90 μL, 518 μmol),(2R)-2-aminopropan-1-ol (40 μL, 518 μmol) and T3P (156 μL, 50% in DMF)was stirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (27 mg, 37%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03 (3H), 2.37 (1H), 2.53 (1H),2.93-3.12 (3H), 3.24 (1H), 3.36 (1H), 3.77 (1H), 4.71 (1H), 6.58 (2H),6.63 (1H), 7.04 (2H), 7.45 (1H), 7.46 (2H), 7.79 (1H), 8.41 (2H), 11.96(1H)

Example 135(6RS)—N-[2-(Methylamino)ethyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (89 μL, 518 μmol),N-methylethane-1,2-diamine (45 μL, 518 μmol) and T3P (156 μL, 50% inDMF) was stirred at RT for 1 day. The mixture was filtered and purifiedby preparative HPLC (basic method) to give the title compound (19 mg,25%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.35 (3H), 2.42 (1H), 2.55 (1H), 2.65(2H), 2.99-3.13 (3H), 3.21 (2H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.45(1H), 7.47 (2H), 8.13 (1H), 8.32 (1H), 8.42 (2H), 12.02 (1H)

Example 136N-[(6RS)-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-L-prolinamide

A mixture comprising tert-butyl(2S)-2-([(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamoyl)pyrrolidine-1-carboxylate(90; 82 mg, 155 μmol), TFA (179 μL, 2.32 mmol) and DCM (5 mL) wasstirred at RT for 16 h. The mixture was poured into ammonia (25% inwater), extracted with DM/MeOH, the organic layer was washed with waterand dried over sodium sulfate. After filtration and concentration, theresidue was purified by preparative HPLC (basic method) to give thetitle compound (49 mg, 70%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.61 (2H), 1.86 (1H), 1.96 (1H),2.17-2.31 (2H), 2.38 (1H), 2.60 (1H), 2.78-2.93 (3H), 3.11-3.27 (2H),3.53 (1H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.43 (1H), 7.46 (2H), 8.11(1H), 8.41 (2H), 11.92 (1H)

Example 137 tert-Butylmethyl(3-oxo-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]aminopropyl)carbamate

A mixture comprising4-[(6RS)-6-ammonio-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridiniumchloride (5; 40 mg, 102 μmol), DMF (1.5 mL), DIPEA (107 μL, 613 μmol),N-(tert-butoxycarbonyl)-N-methyl-beta-alanine (62 mg, 307 μmol) and T3P(184 μL, 50% in DMF) was stirred at RT for 2 h. The mixture was filteredand purified by preparative HPLC (basic method) to give the titlecompound (21 mg, 39%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39 (9H), 2.29 (2H), 2.43 (1H), 2.53(1H), 2.76 (3H), 2.85 (1H), 3.16 (1H), 3.36 (2H), 4.31 (1H), 6.60 (2H),6.63 (1H), 7.04 (2H), 7.45 (1H), 7.46 (2H), 8.33 (1H), 8.42 (2H), 11.96(1H)

Example 138 Methyl(6RS)-2-[2-[rel-(1R,2R)-2-fluorocyclopropyl]carbonylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate

A solution of rel-(1R,2R)-2-fluorocyclopropanecarboxylic acid (318 mg,3.06 mmol) and HATU (1.16 g, 3.06 mmol) in DMF (1 mL) was added to amixture of methyl(6RS)-2-(2-aminopyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate(31; 500 mg, 1.33 mmol) and DIPEA (532 μL, 3.06 mmol) in DMF (1 mL) andthe reaction was stirred at 50° C. for 16 h. MeOH was added, the mixtureconcentrated and purified by Biotage (SNAP silica 50 g, MeOH:DCM) togive the title compound (812 mg, max. 100%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.26 (2H), 1.64 (1H), 2.20 (1H), 2.52(1H), 2.58 (1H), 3.08-3.21 (2H), 3.64 (3H), 4.94 (1H), 6.55 (2H), 6.60(1H), 7.02 (2H), 7.16 (1H), 7.39 (1H), 8.09 (1H), 8.26 (1H), 10.74 (1H),12.04 (1H)

Example 139(6RS)-6-[(1,3-Benzothiazol-2-ylsulfonyl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture comprising(6RS)-6-[(1,3-benzothiazol-2-ylsulfanyl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one(67; 115 mg, 238 μmol), mCPBA (50 mg, 75%) and DMA (7 mL) was stirred atRT. After 4 h a second portion mCPBA (25 mg, 75%) was added and after 4h a third portion mCPBA (25 mg, 75%). The mixture was stirred at RT for4 h, Et₃N (400 μL) was added, the mixture concentrated and purified bypreparative HPLC (basic method) to give the title compound (5 mg, 4%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.42-2.56 (2H), 2.85-2.98 (2H), 3.29(1H), 3.96 (1H), 4.05 (1H), 6.57 (2H), 6.62 (1H), 7.04 (2H), 7.42 (1H),7.46 (2H), 7.69-7.76 (2H), 8.27 (1H), 8.37 (1H), 8.41 (2H), 12.01 (1H)

Example 140(6RS)-2-[2-([rel-(1R,2R)-2-Fluorocyclopropyl]carbonylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid

A mixture of methyl methyl(6RS)-2-[2-([rel-(1R,2R)-2-fluorocyclopropyl]carbonylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate(138; 614 mg, 1.33 mmol), potassium hydroxide (5.3 mL, 4M in water), THF(5.4 mL) and MeOH (5.4 mL) was stirred at RT for 10 minutes.Hydrochloric acid (6 mL, 3M) was added and the mixture concentrated. Theprecipitate was washed with water and dried to give the title compound(452 mg, 76%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 (1H), 1.64 (1H), 2.20 (1H),2.48-2.59 (2H), 3.06-3.25 (3H), 4.94 (1H), 6.56 (2H), 6.60 (1H), 7.01(2H), 7.15 (1H), 7.39 (1H), 8.09 (1H), 8.26 (1H), 10.73 (1H), 12.02(1H), 12.60 (1H)

Example 141(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid 141-4: methyl(1RS)-3-hydroxy-1-methyl-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate

To a solution of methyl(1RS)-3-hydroxy-1-methyl-5-oxocyclohex-3-ene-1-carboxylate (6.98 g, 37.9mmol; can be prepared according to Australian Journal of Chemistry,1989, 42(8), 1217-1225) and phenylisothiocyanate (5.44 mL, 45.5 mmol) inMeCN (75 mL) at 3° C. was added DBU (6.79 mL, 45.5 mmol) and the mixturewas stirred at 3° C. for 16 h. The mixture was poured into water (1 L),hydrochloric acid (10 mL, 4M) was added, the mixture was extracted withethyl acetate, the organic layer was washed with water and brine anddried over sodium sulfate. After filtration the mixture was concentratedand dried to give the title compound (8.55 g, 71%).

141-3: Methyl(1RS)-3-{[(2-aminopyridin-4-yl)methyl]amino}-1-methyl-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate

A solution of methyl(1RS)-3-hydroxy-1-methyl-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate(141-3; 8.55 g, 26.8 mmol) and 4-(methylamino)pyridine (5.94 g, 48.2mmol) in DMA (75 mL) was heated at 100° C. for 1 h. The mixture waspoured into water (1 L), extracted with DCM, the organic layer waswashed with water and brine and dried over sodium sulfate. Afterfiltration the mixture was concentrated and purified by Biotage (SNAPsilica 340 g, MeOH:DCM) to give the title compound (8.67 g, 76%).

141-2: Methyl(6RS)-2-(2-aminopyridin-4-yl)-3-anilino-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate

A mixture of methyl(1RS)-3-{[(2-aminopyridin-4-yl)methyl]amino}-1-methyl-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate(141-3; 6.07 g, 14.3 mmol), hydrogen peroxide (30% in water, 5.84 mL,57.2 mmol) in MeOH (272 mL) was heated at 50° C. for 3 h. The mixturewas concentrated and purified by Biotage (SNAP silica 110 g, MeOH:DCM)to give the title compound (3.19 g, 57%).

141-1: Methyl(6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate

To a solution of methyl(6RS)-2-(2-aminopyridin-4-yl)-3-anilino-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate(141-2; 1.60 g, 4.1 mmol) in THF (54 mL) and pyridine (2.86 mL) wasadded the solution of acetyl chloride (437 μL, 6.15 mmol) in THF (10 mL)over 20 minutes and the mixture was stirred at RT for 1 h. MeOH wasadded, the mixture concentrated and purified by Biotage (SNAP silica 100g, MeOH:DCM) to give the title compound (1.48 g, 84%).

(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid

A mixture of methyl(6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate(141-1; 1.48 g, 3.42 mmol), lithium hydroxide (20.5 mL, 1M in water),THF (61 mL) and MeOH (19 mL) was stirred at RT for 3 h. Citric acid(1.38 g) in water (20 mL) was added and the mixture concentrated. Theprecipitate was washed with water and dried to give the title compound(1.19 g, 77%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (3H), 2.07 (3H), 2.41 (1H), 2.64(1H), 2.85 (1H), 3.31 (1H), 6.54 (2H), 6.59 (1H), 7.00 (2H), 7.14 (1H),7.37 (1H), 8.08 (1H), 8.21 (1H), 10.35 (1H), 11.95 (1H), 12.59 (1H)

Example 142 Methyl(6RS)-2-2-[(4-fluorobenzoyl)amino]pyridin-4-yl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate

A solution of 4-fluorobenzoic acid (428 mg, 3.06 mmol) and HATU (1.16 g,3.06 mmol) in DMF (2 mL) was added to a mixture of methyl(6RS)-2-(2-aminopyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate(31; 500 mg, 1.33 mmol) and DIPEA (532 μL, 3.06 mmol) in DMF (2 mL) andthe reaction was stirred at 50° C. for 16 h. MeOH and EtOAc were added,the mixture washed with saturated sodium hydrogencarbonate solution,concentrated and purified by Biotage (SNAP silica 100 g, MeOH:DCM) togive the title compound (603 mg, 91%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.55-2.63 (2H), 3.10-3.23 (2H), 3.37(1H), 3.65 (3H), 6.58 (2H), 6.61 (1H), 7.03 (2H), 7.24 (1H), 7.36 (2H),7.43 (1H), 8.11 (2H), 8.18 (1H), 8.34 (1H), 10.76 (1H), 12.08 (1H)

Example 143 Methyl(6RS)-4-oxo-3-(phenylamino)-2-2-[(1,3-thiazol-5-ylcarbonyl)amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indol-6-carboxylate

A solution of 1,3-thiazole-5-carboxylic acid (395 mg, 3.06 mmol) andHATU (1.16 g, 3.06 mmol) in DMF (2 mL) was added to a mixture of methyl(6RS)-2-(2-aminopyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate(31; 500 mg, 1.33 mmol) and DIPEA (532 μL, 3.06 mmol) in DMF (2 mL) andthe reaction was stirred at 50° C. for 16 h. MeOH and EtOAc were added,the mixture washed with saturated sodium hydrogencarbonate solution,concentrated and purified by Biotage (SNAP silica 100 g, MeOH:DCM) togive the title compound (645 mg, 90%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.54-2.65 (2H), 3.09-3.22 (2H), 3.37(1H), 3.64 (3H), 6.58 (2H), 6.61 (1H), 7.02 (2H), 7.25 (1H), 7.44 (1H),8.20 (1H), 8.30 (1H), 8.88 (1H), 9.33 (1H), 11.12 (1H), 12.07 (1H)

Example 1443,3-Dimethyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide

A mixture of4-[(6RS)-6-ammonio-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridiniumchloride (5; 40 mg, 102 μmol), 3,3-dimethylbutanoyl chloride (28 μL, 204μmol) in pyridine (2 mL) was stirred at RT for 16 h. The mixture wasconcentrated and purified by Biotage (SNAP silica 50 g, MeOH:DCM) togive the title compound (14 mg, 33%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.94 (9H), 1.96 (2H), 2.43 (1H), 2.52(1H), 2.87 (1H), 3.15 (1H), 4.32 (1H), 6.59 (2H), 6.63 (1H), 7.04 (2H),7.45 (1H), 7.46 (2H), 8.12 (1H), 8.42 (2H), 11.96 (1H)

Example 145(6RS)-2-2-[(4-Fluorobenzoyl)amino]pyridin-4-yl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid

A mixture of methyl(6RS)-2-2-[(4-fluorobenzoyl)amino]pyridin-4-yl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate(142; 527 mg, 1.06 mmol), potassium hydroxide (4.2 mL, 4M in water), THF(4.2 mL) and MeOH (4.2 mL) was stirred at RT for 10 minutes.Hydrochloric acid (5.6 mL, 3M) was added and the mixture concentrated.The precipitate was washed with water and dried to give the titlecompound (450 mg, 88%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.53-2.63 (2H), 3.08-3.27 (3H), 6.59(2H), 6.61 (1H), 7.02 (2H), 7.24 (1H), 7.36 (2H), 7.43 (1H), 8.11 (2H),8.18 (1H), 8.34 (1H), 10.75 (1H), 12.05 (1H), 12.62 (1H)

Example 146(6RS)-Oxo-3-(phenylamino)-2-2-[(1,3-thiazol-5-ylcarbonyl)amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid

A mixture of methyl(6RS)-4-oxo-3-(phenylamino)-2-2-[(1,3-thiazol-5-ylcarbonyl)amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indol-6-carboxylate(143; 625 mg, 1.28 mmol), potassium hydroxide (5.1 mL, 4M in water), THF(5.1 mL) and MeOH (5.1 mL) was stirred at RT for 10 minutes.Hydrochloric acid (6.8 mL, 3M) was added and the mixture concentrated.The precipitate was washed with water and dried to give the titlecompound (480 mg, 79%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.52-2.62 (2H), 3.07-3.26 (3H), 6.58(2H), 6.61 (1H), 7.02 (2H), 7.25 (1H), 7.44 (1H), 8.20 (1H), 8.29 (1H),8.88 (1H), 9.33 (1H), 11.11 (1H), 12.05 (1H), 12.62 (1H)

Example 147

N³-Methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]-beta-alaninamidetrifluoroacetate

A solution of tert-butylmethyl(3-oxo-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]aminopropyl)carbamate(137; 20 mg, 40 μmol) in TFA (2.5 mL) was stirred at RT for 1 h,concentrated and dried to give the title compound (23 mg, 100%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.47-2.58 (5H), 2.64 (1H), 2.93 (1H),3.10 (2H), 3.24 (1H), 4.41 (1H), 6.72 (2H), 6.77 (1H), 7.13 (2H), 7.73(2H), 8.06 (1H), 8.31 (2H), 8.57 (1H), 8.61 (2H), 12.50 (1H)

Example 148(6RS)—N-[(1-Hydroxycyclobutyl)methyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (90 μL, 518 μmol),1-(aminomethyl)cyclobutanol (52 mg, 518 μmol) and T3P (156 μL, 50% inDMF) was stirred at RT for 1 h. The mixture was concentrated andpurified by preparative HPLC (basic method) to give the title compound(40 mg, 54%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.42 (1H), 1.61 (1H), 1.84-1.97 (4H),2.37 (1H), 2.56 (1H), 2.94-3.10 (2H), 3.16-3.27 (3H), 5.17 (1H), 6.58(2H), 6.63 (1H), 7.04 (2H), 7.45 (1H), 7.46 (2H), 7.97 (1H), 8.41 (2H),11.96 (1H)

Example 149(4E)-5-[(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-yl]pent-4-enoicacid 149-1:N-{4-[(6RS)-3-Anilino-6-formyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl)}acetamide

A solution of ethanedioyl dichloride (196 μL, 2.25 mmol) in DCM (6 mL)was cooled to −78° C. DMSO (318 μL, 4.50 mmol) was added slowly followedby a solution ofN-4-[(6RS)-6-(hydroxymethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide(94; 350 mg, 896 μmol) in DCM (6 mL). The mixture was stirred at −78° C.for 1 h, Et₃N (1.0 mL) was added and the mixture warmed to RT. Water wasadded, the mixture extracted with DCM/MeOH and dried over sodiumsulfate. After filtration and concentration the residue was purified byBiotage (SNAP silica 25 g, MeOH:DCM) to give the title compound (69 mg,20%).

(4E)-5-[(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-yl]pent-4-enoicacid

To a solution of (3-carboxypropyl)(triphenyl)phosphonium bromide (790mg, 1.84 mmol) in THF (12 mL) was added KO^(t)Bu (413 mg, 3.68 mmol) at0° C. and the mixture stirred at 0° C. to RT for 0.5 h. A solution ofN-{4-[(6RS)-3-Anilino-6-formyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide(149-1; 143 mg, 368 μmol) in THF (5 mL) was added at 0° C. and themixture stirred for 2 h. Water and EtOAc were added, the mixture washedwith brine and dried over sodium sulfate. After filtration andconcentration the residue was purified by Biotage (SNAP silica 25 g,MeOH:DCM) followed ba preparative TLC (MeOH:DCM) to give the titlecompound (38 mg, 20%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.59 (1H), 2.06 (3H), 2.10-2.39 (6H),2.69 (1H), 2.92 (1H), 5.34-5.44 (2H), 6.57 (2H), 6.60 (1H), 7.01 (2H),7.17 (1H), 7.35 (1H), 8.08 (1H), 8.22 (1H), 10.33 (1H), 12.02 (1H)

Example 150 Methyl(6RS)-2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate150-1: Methyl(1RS)-3-({[3-(2,2-difluoroethoxy)pyridin-4-yl]methyl}amino)-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate

A solution of methyl(1RS)-5-oxo-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-ene-1-carboxylate(8-2; 863 mg, 2.83 mmol) and1-[3-(2,2-difluoroethoxy)pyridin-4-yl]methanamine (638 mg, 3.39 mmol;commercially available e.g. from UkrOrgSynthesis Ltd.) in DMA (12 mL)was heated at 130° C. for 1 h. The mixture was concentrated and purifiedby Biotage (SNAP silica 50 g, EtOAc:Hexane) to give the title compound(660 mg, 49%).

Methyl(6RS)-2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate

A mixture of methyl(1RS)-3-({[3-(2,2-difluoroethoxy)pyridin-4-yl]methyl}amino)-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate(150-1; 510 mg, 1.07 mmol), hydrogen peroxide (34% in water, 193 μL,2.15 mmol) in MeOH (7.9 mL) was heated at 80° C. for 1 h. The mixturewas concentrated and purified by Biotage (SNAP silica 25 g,EtOAc:Hexane) to give the title compound (140 mg, 30%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.57-2.66 (2H), 3.10 (1H), 3.18 (1H),3.37 (1H), 3.65 (3H), 4.33 (2H), 6.33 (1H), 6.51 (2H), 6.57 (1H), 6.96(2H), 7.29 (1H), 7.44 (1H), 8.13 (1H), 8.38 (1H), 11.40 (1H)

Example 151N-4-[(6RS)-6-(Azidomethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide151-1:[(6RS)-2-(2-Acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate

A solution ofN-4-[(6RS)-6-(hydroxymethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide(94; 1.18 g, 3.01 mmol), DMAP (37 mg, 0.3 mmol) and methanesulfonylchloride (280 μL, 3.61 mmol) in pyridine (16 mL) was stirred at RT for 5h. MeOH was added, the mixture concentrated and purified bycrystallization from MeOH to give the title compound (1.26 g, 90%).

N-4-[(6RS)-6-(Azidomethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide

A mixture of[(6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (151-1; 200 mg, 427 μmol), sodium azide (278 mg, 4.27mmol) in DMA (8 mL) was stirred at 60° C. for 16 h. The mixture wasfiltered, concentrated and purified by Biotage (SNAP silica 10 g,MeOH:DCM) to give the title compound (164 mg, 88%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.07 (3H), 2.28 (1H), 2.35 (1H), 2.47(1H), 2.69 (1H), 3.02 (1H), 3.50 (2H), 6.56 (2H), 6.60 (1H), 7.01 (2H),7.15 (1H), 7.36 (1H), 8.08 (1H), 8.23 (1H), 10.35 (1H), 11.97 (1H)

Example 152(6RS)—N-(2-Methoxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (89 μL, 518 μmol),2-methoxy-N-methylethanamine (56 μL, 518 μmol) and T3P (156 μL, 50% inDMF) was stirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (45 mg, 59%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.27-2.35 (1H), 2.47-2.57 (1H),2.86+3.09 (3H), 2.91-3.06 (2H), 3.25+3.27 (3H), 3.39-3.51 (3H),3.56-3.70 (2H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.42-7.48 (3H), 8.41(2H), 11.95 (1H)

Example 153(6RS)-2-[2-([rel-(1R,2R)-2-Fluorocyclopropyl]carbonylamino)pyridin-4-yl]-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising(6RS)-2-[2-([rel-(1R,2R)-2-fluorocyclopropyl]carbonylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (140; 60 mg, 134 μmol), DMF (2 mL), DIPEA (70 μL, 401 μmol),2-(methylamino)ethanol (32 μL, 401 μmol) and T3P (120 μL, 50% in DMF)was stirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (38 mg, 56%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 (1H), 1.64 (1H), 2.20 (1H), 2.32(1H), 2.46-2.57 (1H), 2.85+3.10 (3H), 2.92-3.03 (2H), 3.28-3.55 (4H),3.61+3.70 (1H), 4.55-4.95 (1H), 4.85+5.02 (1H), 6.58 (2H), 6.61 (1H),7.02 (2H), 7.16 (1H), 7.36+7.37 (1H), 8.08 (1H), 8.26 (1H), 10.73 (1H),11.98 (1H)

Example 154(6RS)-2-[2-([rel-(1R,2R)-2-Fluorocyclopropyl]carbonylamino)pyridin-4-yl]-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising(6RS)-2-[2-([rel-(1R,2R)-2-fluorocyclopropyl]carbonylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (140; 60 mg, 134 μmol), DMF (2 mL), DIPEA (70 μL, 401 μmol),N-methylmethanamine (201 μL, 2M in THF) and T3P (124 μL, 50% in DMF) wasstirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (37 mg, 58%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 (1H), 1.64 (1H), 2.20 (1H), 2.31(1H), 2.49 (1H), 2.85 (3H), 2.92-3.03 (2H), 3.06 (3H), 3.64 (1H), 4.93(1H), 6.58 (2H), 6.61 (1H), 7.02 (2H), 7.15 (1H), 7.37 (1H), 8.08 (1H),8.26 (1H), 10.73 (1H), 11.98 (1H)

Example 155(6RS)—N-(2,2-Dimethylpropyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (180 μL, 1.04 mmol),N,2,2-trimethylpropan-1-amine hydrochloride (71 mg, 518 μmol) and T3P(156 μL, 50% in DMF) was stirred at RT for 1 h. The mixture was filteredand purified by preparative HPLC (basic method) to give the titlecompound (59 mg, 79%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.88+0.92 (9H), 2.24+2.36 (1H),2.42-2.61 (1H), 2.91+3.14 (3H), 2.95-3.07 (2H), 3.13-3.30 (2H), 3.68(1H), 6.59 (2H), 6.63 (1H), 7.5 (2H), 7.44 (1H), 7.46 (2H), 8.41 (2H),11.95 (1H)

Example 156N-4-[(6RS)-6-(Aminomethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide

A mixture ofN-4-[(6RS)-6-(azidomethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide(151; 155 mg, 373 μmol), triphenylphosphine (218 mg, 832 μmol) ammonia(798 μL, 25% in water) in THF (5.5 mL) was stirred at RT for 16 h. Themixture was concentrated and purified by Biotage (SNAP silica 28 g,MeOH:DCM) to give the title compound (129 mg, 86%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.07 (3H), 2.16-2.26 (2H), 2.36 (1H),2.58-2.67 (3H), 2.97 (1H), 6.56 (2H), 6.60 (1H), 7.01 (2H), 7.15 (1H),7.35 (1H), 8.07 (1H), 8.22 (1H), 10.34 (1H), 11.91 (1H)

Example 157 Methyl(6RS)-3-anilino-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate157-1: Methyl3-({[3-(cyclopropylmethoxy)pyridin-4-yl]methyl}amino)-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate

A solution of methyl(1RS)-3-hydroxy-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate(8-2; 50 mg, 164 μmol) and1-[3-(cyclopropylmethoxy)pyridin-4-yl]methanamine (157-2; 25 mg, 196μmol; commercially available e.g. from UkrOrgSynthesis Ltd.) in DMA (0.7mL) was heated at 1300 for 1 h. The mixture was concentrated andpurified by preparative HPLC (basic method) to give the title compound(75 mg, 98%).

Methyl(6RS)-3-anilino-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate

A mixture of methyl3-({[3-(cyclopropylmethoxy)pyridin-4-yl]methyl}amino)-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate(157-1; 450 mg, 967 μmol), hydrogen peroxide (34% in water, 174 μL, 1.93mmol) in MeOH (7.1 mL) was heated at 90° C. for 5.5 h. Saturated sodiumthiosulphate solution was added, the mixture concentrated and purifiedby Biotage (SNAP silica 25 g, MeOH:DCM) to give the title compound (110mg, 26%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.34 (2H), 0.56 (2H), 1.29 (1H),2.54-2.65 (2H), 3.07-3.21 (2H), 3.36 (1H), 3.65 (3H), 3.94 (2H), 6.52(2H), 6.57 (1H), 6.97 (2H), 7.27 (1H), 7.36 (1H), 8.04 (1H), 8.33 (1H),11.37 (1H)

Example 158(6RS)-3-Anilino-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid

A mixture of methyl(6RS)-3-anilino-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate(157; 104 mg, 241 μmol), potassium hydroxide (964 μL, 4M in water), THF(1 mL) and MeOH (1 mL) was stirred at RT for 10 minutes. Hydrochloricacid (1.26 mL, 3M) was added and the mixture concentrated. Theprecipitate was washed with water and dried to give the title compound(45 mg, 45%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.34 (2H), 0.56 (2H), 1.29 (1H),2.49-2.63 (2H), 3.06-3.18 (2H), 3.24 (1H), 3.93 (2H), 6.52 (2H), 6.57(1H), 6.97 (2H), 7.28 (1H), 7.39 (1H), 8.05 (1H), 8.32 (1H), 11.35 (1H),12.58 (1H)

Example 159(6RS)-2-[3-(Cyclopropylmethoxy)pyridin-4-yl]-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising(6RS)-3-Anilino-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (158; 30 mg, 72 μmol), DMF (0.8 mL), DIPEA (38 μL, 216 μmol),2-(methylamino)ethanol (17 μL, 216 μmol) and T3P (65 μL, 50% in DMF) wasstirred at RT for 1 h. The mixture was concentrated and purified bypreparative HPLC (basic method) to give the title compound (32 mg, 94%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.35 (2H), 0.56 (2H), 1.29 (1H),2.30-2.37 (1H), 2.48-2.58 (1H), 2.86+3.11 (3H), 2.92-3.04 (2H),3.31-3.56 (4H), 3.65+3.73 (1H), 3.88-3.97 (2H), 4.68+4.85 (1H), 6.54(2H), 6.57 (1H), 6.98 (2H), 7.27 (1H), 7.36+7.37 (1H), 8.04 (1H), 8.31(1H), 11.31 (1H)

Example 160 Methyl(6RS)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate160-1: Methyl(1RS)-3-({[3-(2-methoxyethoxy)pyridin-4-yl]methyl}amino)-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate

A solution of methyl(1RS)-3-hydroxy-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate(8-2; 700 mg, 2.29 mmol) and1-[3-(2-methoxyethoxy)pyridin-4-yl]methanamine (160-2; 584 mg, 3.21mmol; commercially available e.g. from UkrOrgSynthesis Ltd.) in DMA (10mL) was heated at 130° C. for 1 h. The mixture was concentrated andpurified by Biotage (SNAP silica 50 g, MeOH:DCM) to give the titlecompound (515 mg, 48%).

Methyl(6RS)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate

A mixture of methyl(1RS)-3-({[3-(2-methoxyethoxy)pyridin-4-yl]methyl}amino)-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate(160-1; 460 mg, 980 μmol), hydrogen peroxide (34% in water, 177 μL, 1.96mmol) in MeOH (7.2 mL) was heated at 90° C. for 5.5 h. Saturated sodiumthiosulphate solution was added, the mixture concentrated and purifiedby Biotage (SNAP silica 25 g, MeOH:DCM) to give the title compound (165mg, 39%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.54-2.66 (2H), 3.07-3.20 (2H), 3.36(1H), 3.38 (3H), 3.65 (3H), 3.75 (2H), 4.28 (2H), 6.53 (2H), 6.58 (1H),6.98 (2H), 7.30 (1H), 7.39 (1H), 8.05 (1H), 8.39 (1H), 11.28 (1H)

Example 161(6RS)-3-Anilino-2-[3-(2-methoxyethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid

A mixture of methyl(6RS)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate(160; 121 mg, 278 μmol), potassium hydroxide (1.11 mL, 4M in water), THF(1.1 mL) and MeOH (1.1 mL) was stirred at RT for 10 minutes.Hydrochloric acid (1.5 mL, 3M) was added and the mixture concentrated.The precipitate was washed with water and dried to give the titlecompound (100 mg, 85%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.51-2.63 (2H), 3.06-3.17 (2H), 3.24(1H), 3.39 (3H), 3.75 (2H), 4.29 (2H), 6.53 (2H), 6.58 (1H), 6.98 (2H),7.30 (1H), 7.40 (1H), 8.04 (1H), 8.39 (1H), 11.25 (1H), 12.60 (1H)

Example 162(6RS)-2-[3-(2-Methoxyethoxy)pyridin-4-yl]-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising(6RS)-3-anilino-2-[3-(2-methoxyethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (161; 30 mg, 71 μmol), DMF (1.1 mL), DIPEA (37 μL, 213 μmol),N-methylmethanamine (107 μL, 2M in THF) and T3P (64 μL, 50% in DMF) wasstirred at RT for 1 h. The mixture was concentrated and purified bypreparative HPLC (basic method) to give the title compound (30 mg, 94%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.33 (1H), 2.51 (1H), 2.85 (3H),2.91-3.05 (2H), 3.07 (3H), 3.38 (3H), 3.68 (1H), 3.75 (2H), 4.29 (2H),6.56 (2H), 6.59 (1H), 6.99 (2H), 7.30 (1H), 7.39 (1H), 8.04 (1H), 8.39(1H), 11.20 (1H)

Example 163(6RS)—N-(2-Hydroxyethyl)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-N-methyl-4-oxo-3-(phenylamine)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising(6RS)-3-anilino-2-[3-(2-methoxyethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (161; 30 mg, 71 μmol), DMF (0.8 mL), DIPEA (37 μL, 213 μmol),2-(methylamino)ethanol (16 mg, 214 μmol) and T3P (64 μL, 50% in DMF) wasstirred at RT for 1 h. The mixture was concentrated and purified bypreparative HPLC (basic method) to give the title compound (30 mg, 88%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.30-2.38 (1H), 2.48-2.59 (1H),2.86+3.11 (3H), 2.91-3.06 (2H), 3.31-3.56 (4H), 3.38 (3H), 3.61-3.77(3H), 4.28 (2H), 4.68+4.86 (1H), 6.55 (2H), 6.59 (1H), 6.99 (2H),7.29-7.33 (1H), 7.39 (1H), 8.04 (1H), 8.39 (1H), 11.21 (1H)

Example 164 Methyl(6RS)-3-anilino-2-[3-(2-hydroxyethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate164-1: Methyl(1RS)-3-({[3-(2-hydroxyethoxy)pyridin-4-yl]methyl}amino)-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate

A solution of methyl(1RS)-3-hydroxy-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate(8-2; 1.51 g, 4.95 mmol) and 2-{[4-(aminomethyl)pyridin-3-yl]oxy}ethanol(164-2; 1.00 g, 5.95 mmol; commercially available e.g. fromUkrOrgSynthesis Ltd.) in DMA (2 mL) was heated at 130′C for 5 h. Themixture was concentrated and purified by Biotage (SNAP silica 340 g,MeOH:DCM) to give the title compound (352 mg, 16%).

Methyl(6RS)-3-anilino-2-[3-(2-hydroxyethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate

A mixture of methyl(1RS)-3-({[3-(2-hydroxyethoxy)pyridin-4-yl]methyl}amino)-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate(164-1; 387 mg, 850 μmol), hydrogen peroxide (34% in water, 153 μL, 1.70mmol) in MeOH (5 mL) was heated at 90° C. for 24 h. The mixture wasconcentrated and purified by Biotage (SNAP silica 50 g, MeOH:DCM) togive the title compound (133 mg, 37%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.53-2.65 (2H), 3.04-3.19 (2H), 3.37(1H), 3.65 (3H), 3.84 (2H), 4.25 (2H), 5.61 (1H), 6.55 (2H), 6.58 (1H),6.99 (2H), 7.31 (1H), 7.44 (1H), 8.02 (1H), 8.42 (1H), 11.59 (1H)

Example 165(6RS)-2-[3-(2-Hydroxyethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid

A mixture of methyl methyl(6RS)-3-anilino-2-[3-(2-hydroxyethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate(164; 255 mg, 605 μmol), potassium hydroxide (2.42 mL, 4M in water), THF(2.4 mL) and MeOH (2.4 mL) was stirred at RT for 10 minutes.Hydrochloric acid (3.2 mL, 3M) was added and the mixture concentrated.The precipitate was washed with water and dried to give the titlecompound (149 mg, 58%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.48-2.63 (2H), 3.03-3.16 (2H), 3.23(1H), 3.85 (2H), 4.25 (2H), 5.61 (1H), 6.56 (2H), 6.59 (1H), 6.99 (2H),7.31 (1H), 7.44 (1H), 8.02 (1H), 8.42 (1H), 11.57 (1H), 12.62 (1H)

Example 166(6RS)-2-[3-(2,2-Difluoroethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid

A mixture of methyl(6RS)-2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate(150; 510 mg, 1.07 mmol), hydrogen peroxide (34% in water, 193 μL, 2.15mmol) in MeOH (7.9 mL) was heated at 90° C. for 1 h. The mixture wasconcentrated and purified by Biotage (SNAP silica 25 g, MeOH:DCM) togive the title compound (290 mg, 61%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.53-2.66 (2H), 3.06-3.21 (2H), 3.37(1H), 3.65 (3H), 4.33 (2H), 6.33 (1H), 6.51 (2H), 6.57 (1H), 6.96 (2H),7.29 (1H), 7.44 (1H), 8.13 (1H), 8.38 (1H), 11.40 (1H)

Example 167(6RS)—N-Ethyl-N-(2-hydroxyethyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising(6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (90 μL, 518 μmol),2-(ethylamino)ethanol (51 μL, 518 μmol) and T3P (156 μL, 50% in DMF) wasstirred at RT for 1 h. The mixture was concentrated and purified bypreparative HPLC (basic method) to give the title compound (51 mg, 67%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03+1.12 (3H), 1.47+1.75 (1H),2.27+2.32 (1H), 2.48-2.60 (1H), 2.89-3.53 (7H), 3.57+3.68 (1H),4.70+4.85 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.43 (1H), 7.46 (2H),8.41 (2H), 11.96 (1H)

Example 168(6RS)—N-(2-Hydroxyethyl)-4-oxo-3-(phenylamino)-N-(propan-2-yl)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising(6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (90 μL, 518 μmol),2-(isopropylamino)ethanol (83 μL, 518 μmol) and T3P (156 μL, 50% in DMF)was stirred at RT for 1 h. The mixture was concentrated and purified bypreparative HPLC (basic method) to give the title compound (13 mg, 16%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.91-1.17 (6H), 1.41-1.56 (2H),2.26+2.30 (1H), 2.46-2.59 (2H), 2.89-3.70 (5H), 4.21+4.46 (1H),6.56-6.66 (3H), 7.05 (2H), 7.43-7.49 (3H), 8.42 (2H), 11.96+11.99 (1H)

Example 169(6RS)—N-[(1-Hydroxycyclobutyl)methyl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising(6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (90 μL, 518 μmol),1-[(methylamino)methyl]cyclobutanol (60 mg, 518 μmol) and T3P (156 μL,50% in DMF) was stirred at RT for 1 h. The mixture was concentrated andpurified by preparative HPLC (basic method) to give the title compound(52 mg, 61%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.42-2.06 (6H), 2.27-2.37 (1H),2.45-2.59 (1H), 2.90-3.08 (2H), 2.93+3.16 (3H), 3.45-3.54 (2H),3.65-3.81 (1H), 5.18+5.32 (1H), 6.59 (2H), 6.63 (1H), 7.04 (2H),7.43+7.44 (1H), 7.46 (2H), 8.41 (2H), 11.95 (1H)

Example 170(6RS)—N-[(2R)-1-Hydroxypropan-2-yl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising(6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol), DMF (2 mL), DIPEA (90 μL, 518 μmol),(2R)-2-(methylamino)propan-1-ol (65 mg, 518 μmol) and T3P (156 μL, 50%in DMF) was stirred at RT for 1 h. The mixture was concentrated andpurified by preparative HPLC (basic method) to give the title compound(22 mg, 27%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.97+1.08 (3H), 2.23-2.62 (4H),2.68+2.90 (3H), 2.92-3.09 (2H), 3.37-3.47 (1H), 3.57-3.74 (1H),4.07+4.54 (1H), 6.56-6.66 (3H), 7.05 (2H), 7.41-7.50 (3H), 8.39-8.43(2H), 11.96+12.03 (1H)

Example 171(6RS)—N-[(2S)-1-Hydroxypropan-2-yl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising(6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 115 μmol), DMF (2 mL), DIPEA (60 μL, 345 μmol),(2S)-2-(methylamino)propan-1-ol (65 mg, 345 μmol) and T3P (104 μL, 50%in DMF) was stirred at RT for 1 h. The mixture was concentrated andpurified by preparative HPLC (basic method) to give the title compound(22 mg, 41%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.97+1.08 (3H), 2.23-2.59 (4H),2.68+2.90 (3H), 2.92-3.11 (2H), 3.36-3.45 (1H), 3.58-3.75 (1H),4.08+4.54 (1H), 6.55-6.66 (3H), 7.05 (2H), 7.41-7.49 (3H), 8.39-8.43(2H), 11.95+12.00 (1H)

Example 172N-(4-{(6RS)-3-Anilino-6-methyl-6-[(4-methylpiperazin-1-yl)carbonyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)acetamide

A mixture comprising(6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (141; 50 mg, 119 μmol), EtOAc (4 mL), DIPEA (62 μL, 358 μmol),1-methylpiperazine (80 μL, 717 μmol) and T3P (142 μL, 50% in DMF) wasstirred at 40° C. for 16 h. Water was added, the mixture extract ed withEtOAc and dried over sodium sulfate. After filtration and concentrationthe residue was purified by Biotage (SNAP silica 11 g, MeOH:DCM) anddigestion with ether to give the title compound (26 mg, 41%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.40 (3H), 2.07 (3H), 2.16 (3H), 2.25(4H), 2.44 (1H), 2.73 (1H), 2.93 (1H), 3.43 (1H), 3.51 (4H), 6.53 (2H),6.59 (1H), 7.00 (2H), 7.14 (1H), 7.35 (1H), 8.07 (1H), 8.21 (1H), 10.35(1H), 11.87 (1H)

Example 173(6RS)-2-(2-Acetamidopyridin-4-yl)-3-anilino-N,N,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising(6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (141; 50 mg, 119 μmol), EtOAc (4 mL), DIPEA (62 μL, 358 μmol),N-methylmethanamine (358 μL, 2M in THF) and T3P (142 μL, 50% in DMF) wasstirred at 40° C. for 16 h. Water was added, the mixt ure extracted withEtOAc and dried over sodium sulfate. After filtration and concentrationthe residue was purified by Biotage (SNAP silica 11 g, MeOH:DCM) andpreparative TLC (MeOH:DCM) to give the title compound (24 mg, 43%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.40 (3H), 2.07 (3H), 2.45 (1H), 2.78(1H), 2.91 (1H), 2.94 (6H), 3.51 (1H), 6.53 (2H), 6.59 (1H), 7.00 (2H),7.13 (1H), 7.36 (1H), 8.07 (1H), 8.21 (1H), 10.35 (1H), 11.87 (1H)

Example 174N-{4-[(6RS)-3-Anilino-6-{[(2R,63)-2,6-dimethylmorpholin-4-yl]carbonyl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide

A mixture comprising(6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (141; 50 mg, 119 μmol), EtOAc (4 mL), DIPEA (62 μL, 358 μmol),(2R,6S)-2,6-dimethylmorpholine (44 μL, 358 μmol) and T3P (142 μL, 50% inDMF) was stirred at 40° C. for 16 h. Water was added, the mixtureextracted with EtOAc and dried over sodium sulfate. After filtration andconcentration the residue was purified by Biotage (SNAP silica 11 g,MeOH:DCM) and preparative TLC (MeOH:DCM) to give the title compound (18mg, 28%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.09 (6H), 1.41 (3H), 2.07 (3H), 2.46(1H), 2.73 (1H), 2.95 (1H), 3.28-3.47 (5H), 4.12 (2H), 6.53 (2H), 6.59(1H), 7.00 (2H), 7.15 (1H), 7.34 (1H), 8.08 (1H), 8.20 (1H), 10.35 (1H),11.87 (1H)

Example 175N-(4-{(6RS)-3-Anilino-6-[(3-fluoroazetidin-1-yl)carbonyl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)acetamide

A mixture comprising(6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylicacid (141; 50 mg, 119 μmol), EtOAc (4 mL), DIPEA (62 μL, 358 μmol),3-fluoroazetidine (40 mg, 358 μmol) and T3P (142 μL, 50% in DMF) wasstirred at 40° C. for 16 h. Water was added, the mixture extract ed withEtOAc and dried over sodium sulfate. After filtration and concentrationthe residue was purified by Biotage (SNAP silica 11 g, MeOH:DCM) anddigestion with ether to give the title compound (25 mg, 42%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.30 (3H), 2.07 (3H), 2.47 (1H), 2.64(1H), 2.81 (1H), 3.39 (1H), 3.84 (1H), 4.13 (1H), 4.44 (1H), 4.71 (1H),5.36 (1H), 6.54 (2H), 6.59 (1H), 7.01 (2H), 7.15 (1H), 7.39 (1H), 8.09(1H), 8.21 (1H), 10.36 (1H), 11.92 (1H)

Example 176N-(4-{(6RS)-3-Anilino-6-[(3,3-difluoroazetidin-1-yl)carbonyl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)acetamide

A mixture comprising(6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (141; 50 mg, 119 μmol), EtOAc (4 mL), DIPEA (62 μL, 358 μmol),3,3-difluoroazetidine (46 mg, 358 μmol) and T3P (142 μL, 50% in DMF) wasstirred at 40° C. for 16 h. Water was added, the mixture extracted withEtOAc and dried over sodium sulfate. After filtration and concentrationthe residue was purified by Biotage (SNAP silica 11 g, MeOH:DCM) to givethe title compound (22 mg, 36%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (3H), 2.07 (3H), 2.54 (1H), 2.64(1H), 2.85 (1H), 3.39 (1H), 4.32 (2H), 4.76 (2H), 6.53 (2H), 6.59 (1H),7.00 (2H), 7.15 (1H), 7.39 (1H), 8.09 (1H), 8.21 (1H), 10.37 (1H), 11.92(1H)

Example 177(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-(2-methoxyethyl)-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A solution of(6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (141; 50 mg, 119 μmol) and HATU (68 mg, 179 μmol) in DMA (1 mL) wasadded to a mixture of 2-methoxy-N-methylethanamine (16 μL, 143 μmol) andDIPEA (25 μL, 143 μmol) in DMA (1 mL) and the reaction was stirred at RTfor 3 h. The mixture was concentrated and purified by preparative HPLC(basic method) and preparative TLC (MeOH:DCM) to give the title compound(26 mg, 41%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.40 (3H), 2.07 (3H), 2.42 (1H), 2.75(1H), 2.92 (1H), 3.08 (2H), 3.12 (3H), 3.22-3.41 (4H), 3.44-3.55 (2H),6.54 (2H), 6.59 (1H), 7.00 (2H), 7.13 (1H), 7.34 (1H), 8.07 (1H), 8.21(1H), 10.34 (1H), 11.86 (1H)

Example 178(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N,N-diethyl-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A solution of(6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (141; 50 mg, 119 μmol) and HATU (91 mg, 239 μmol) in DMA (1 mL) wasadded to a mixture of N-ethylethanaminium chloride (39 mg, 358 μmol) andDIPEA (125 μL, 717 μmol) in DMA (1 mL) and the reaction was stirred atRT for 3 h. The mixture was concentrated and purified by preparativeHPLC (basic method) and preparative TLC (MeOH:DCM) to give the titlecompound (23 mg, 39%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.01 (6H), 1.39 (3H), 2.07 (3H), 2.45(1H), 2.72 (1H), 2.91 (1H), 3.30 (4H), 3.42 (1H), 6.53 (2H), 6.58 (1H),6.99 (2H), 7.14 (1H), 7.33 (1H), 8.07 (1H), 8.20 (1H), 10.34 (1H), 11.87(1H)

Example 179N-4-[(6RS)-6-Methyl-6-(2-oxa-6-azaspiro[3.3]hept-6-ylcarbonyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide

A solution of(6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (141; 50 mg, 119 μmol) and HATU (91 mg, 239 μmol) in DMA (0.9 mL)was added to a mixture of 2-oxa-6-azaspiro[3.3]heptane (52 mg, 358 μmol)and DIPEA (167 μL, 956 μmol) in DMA (0.9 mL) and the reaction wasstirred at RT for 3 h. The mixture was concentrated and purified bypreparative HPLC (basic method) and preparative TLC (MeOH:DCM) to givethe title compound (14 mg, 23%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27 (3H), 2.07 (3H), 2.45 (1H), 2.62(1H), 2.78 (1H), 3.37 (1H), 3.97 (2H), 4.56 (2H), 4.64 (4H), 6.53 (2H),6.59 (1H), 7.00 (2H), 7.14 (1H), 7.37 (1H), 8.08 (1H), 8.21 (1H), 10.35(1H), 11.90 (1H)

Example 180(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-[(2S)-2-methoxypropyl]-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide180-2: tert-Butyl [(2S)-2-methoxypropyl]methylcarbamate

From 1.83 g sodium hydride (60%) the mineral oil was removed and THF (60mL) was added followed by iodomethane (2.84 mL, 45.7 mmol) andtert-butyl [(2R)-2-hydroxypropyl]carbamate (CAS-No: 119768-44-4; 2.00 g,11.4 mmol) solved in THF (10 mL). The mixture was stirred at RT for 4 h,methanol was added and the solvents were removed. Dichloromethane wasadded, the suspension was filtered through silica gel and concentratedto give 960 mg (34%) of the title compound.

180-1: (2S)-2-Methoxy-N-methylpropan-1-aminium chloride

A mixture comprising tert-butyl [(2S)-2-methoxypropyl]methylcarbamate(180-2; 960 mg, 4.72 mmol) and hydrochloric acid (14 mL, 4M in dioxane)was heated at 50° C. for 16 hours. The solvents were removed, theresidue digested with diethyl ether and the precipitate was dried togive 425 mg (61%) of the title compound.

(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-[(2S)-2-methoxypropyl]-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A solution of(6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (141; 50 mg, 119 μmol) and HATU (91 mg, 239 μmol) in DMA (0.9 mL)was added to a mixture of (2S)-2-methoxy-N-methylpropan-1-aminiumchloride (180-1; 50 mg, 358 μmol) and DIPEA (125 μL, 717 μmol) in DMA(0.9 mL) and the reaction was stirred at RT for 3 h. The mixture wasconcentrated and purified by preparative HPLC (basic method) andpreparative TLC (MeOH:DCM) to give the title compound (20 mg, 31%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80+0.83 (3H), 1.41 (3H), 2.07 (3H),2.38 (1H), 2.76 (1H), 2.94 (1H), 3.03+3.08 (3H), 3.10-3.32 (5H),3.37+3.46 (1H), 3.54+3.58 (1H), 6.54 (2H), 6.59 (1H), 7.00 (2H), 7.12(1H), 7.31+7.32 (1H), 8.06 (1H), 8.19 (1H), 10.34 (1H), 11.85+11.86 (1H)

Example 181(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-[(2S)-1-methoxypropan-2-yl]-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide181-2: tert-Butyl [(2S)-1-methoxypropan-2-yl]methylcarbamate

From 1.83 g sodium hydride (60%) the mineral oil was removed, THF (60mL) was added followed by iodomethane (2.84 mL, 45.7 mmol) andtert-butyl [(2S)-1-methoxypropan-2-yl]methylcarbamate (CAS-No:167938-56-9; 2.00 g, 11.4 mmol) solved in THF (10 mL). The mixture wasstirred at RT for 4 h, methanol was added and the solvents were removed.Dichloromethane was added, the suspension was filtered through silicagel and concentrated to give 1.00 g (38%) of the title compound.

181-1: (2S)-1-Methoxy-N-methylpropan-2-aminium chloride

A mixture comprising tert-butyl[(2S)-1-methoxypropan-2-yl]methylcarbamate (180-2; 1.00 g, 4.92 mmol)and hydrochloric acid (12.3 mL, 4M in dioxane) was heated at 50° C. for16 hours. The solvents were removed, the residue digested with diethylether and the precipitate was dried to give 446 mg (62%) of the titlecompound.

(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-[(2S)-1-methoxypropan-2-yl]-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A solution of(6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (141; 50 mg, 119 μmol) and HATU (91 mg, 239 μmol) in DMA (0.9 mL)was added to a mixture of (2S)-1-methoxy-N-methylpropan-2-aminiumchloride (181-1; 50 mg, 358 μmol) and DIPEA (125 μL, 717 μmol) in DMA(0.9 mL) and the reaction was stirred at RT for 3 h. The mixture wasconcentrated and purified by preparative HPLC (basic method) andpreparative TLC (MeOH:DCM) to give the title compound (22 mg, 34%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.01 (3H), 1.41 (3H), 2.07 (3H),2.39+2.47 (1H), 2.63-3.55 (11H), 4.39+4.45 (1H), 6.53 (2H), 6.58 (1H),6.99 (2H), 7.13 (1H), 7.33 (1H), 8.07 (1H), 8.20 (1H), 10.34 (1H), 11.85(1H)

Example 182(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-(2-methoxy-2-methylpropyl)-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A solution of(6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (141; 50 mg, 119 μmol) and HATU (91 mg, 239 μmol) in DMA (1 mL) wasadded to a mixture of 2-methoxy-N,2-dimethylpropan-1-aminium chloride(30 mg, 195 μmol) and DIPEA (83 μL, 479 μmol) in DMA (1 mL) and thereaction was stirred at RT for 6 h and at 50° C. for 1 h. The mixturewas concentrated and purified by preparative HPLC (basic method) andpreparative TLC (MeOH:DCM) to give the title compound (10 mg, 16%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.69 (3H), 0.85 (3H), 1.43 (3H), 2.07(3H), 2.38 (1H), 2.77 (1H), 2.95 (1H), 3.03 (4H), 3.22 (3H), 3.54-3.62(2H), 6.53 (2H), 6.60 (1H), 6.99 (2H), 7.09 (1H), 7.29 (1H), 8.05 (1H),8.18 (1H), 10.34 (1H), 11.84 (1H)

Example 183(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N,6-dimethyl-4-oxo-3-(phenylamino)-N-propyl-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A solution of(6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (141; 50 mg, 119 μmol) and HATU (91 mg, 239 μmol) in DMA (1 mL) wasadded to a mixture of N-methylpropan-1-amine (18 μL, 179 μmol) and DIPEA(62 μL, 358 μmol) in DMA (1 mL) and the reaction was stirred at RT for 3h. The mixture was concentrated and purified by preparative HPLC (basicmethod) and preparative TLC (MeOH:DCM) to give the title compound (19mg, 32%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.69 (3H), 1.37 (2H), 1.40 (3H), 2.07(3H), 2.42 (1H), 2.76 (1H), 2.91 (1H), 2.99 (3H), 3.11 (1H), 3.29 (1H),3.51 (1H), 6.53 (2H), 6.59 (1H), 6.99 (2H), 7.13 (1H), 7.32 (1H), 8.07(1H), 8.20 (1H), 10.35 (1H), 11.85 (1H)

Example 184(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-(2,2-dimethylpropyl)-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A solution of(6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (141; 45 mg, 108 μmol) and HATU (82 mg, 215 μmol) in DMA (1 mL) wasadded to a mixture of N,2,2-trimethylpropan-1-aminium chloride (44 mg,323 μmol) and DIPEA (112 μL, 645 μmol) in DMA (1 mL) and the reactionwas stirred at RT for 16 h. The mixture was concentrated and purified bypreparative HPLC (basic method) and preparative TLC (MeOH:DCM) to givethe title compound (23 mg, 40%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.63 (9H), 1.42 (3H), 2.07 (3H), 2.39(1H), 2.79 (2H), 2.92 (1H), 3.22 (3H), 3.39 (1H), 3.60 (1H), 6.54 (2H),6.59 (1H), 6.99 (2H), 7.06 (1H), 7.28 (1H), 8.05 (1H), 8.18 (1H), 10.33(1H), 11.83 (1H)

Example 185N-4-[(6RS)-6-[(3R)-3-(Dimethylamino)pyrrolidin-1-yl]carbonyl-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide

A solution of(6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (141; 45 mg, 108 μmol) and HATU (82 mg, 215 μmol) in DMA (1 mL) wasadded to a mixture of (3R)—N,N-dimethylpyrrolidin-3-amine (41 μL, 323μmol) and DIPEA (56 μL, 323 μmol) in DMA (1 mL) and the reaction wasstirred at RT for 3 h. The mixture was concentrated and purified bypreparative HPLC (basic method) and preparative TLC (MeOH:DCM) to givethe title compound (15 mg, 26%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (3H), 1.85-3.55 (10H) 2.07 (3H),2.15 (6H), 3.85 (1H), 6.52 (2H), 6.59 (1H), 7.00 (2H), 7.14 (1H), 7.36(1H), 8.08 (1H), 8.21 (1H), 10.34+10.35 (1H), 11.87 (1H)

Example 186N-4-[(6RS)-6-Methyl-6-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide

A solution of(6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (141; 45 mg, 108 μmol) and HATU (82 mg, 215 μmol) in DMA (1 mL) wasadded to a mixture of (1R,4R)-2-methyl-2,5-diazabicyclo[2.2.1]heptanedihydrochloride (60 mg, 323 μmol) and DIPEA (169 μL, 968 μmol) in DMA (1mL) and the reaction was stirred at RT for 3 h. The mixture wasconcentrated and purified by preparative HPLC (basic method) andpreparative TLC (MeOH:DCM) to give the title compound (11 mg, 19%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (3H), 1.41-1.86 (2H), 2.07 (3H),2.23+2.25 (3H), 2.35-2.61 (2H), 2.69-3.86 (7H), 4.36-4.83 (1H), 6.53(2H), 6.59 (1H), 7.00 (2H), 7.14 (1H), 7.34 (1H), 8.08 (1H), 8.21 (1H),10.34+10.35 (1H), 11.88+11.90 (1H)

Example 187(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N,6-dimethyl-N-(2-methylpropyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A solution of(6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (141; 45 mg, 108 μmol) and HATU (82 mg, 215 μmol) in DMA (1 mL) wasadded to a mixture of N,2-dimethylpropan-1-amine (39 μL, 323 μmol) andDIPEA (56 μL, 323 μmol) in DMA (1 mL) and the reaction was stirred at RTfor 3 h. The mixture was concentrated and purified by preparative HPLC(basic method) and preparative TLC (MeOH:DCM) to give the title compound(16 mg, 29%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.55 (3H), 0.67 (3H), 1.41 (3H), 1.72(1H), 2.07 (3H), 2.38 (1H), 2.77 (1H), 2.81 (1H), 2.92 (1H), 3.10 (3H),3.25 (1H), 3.56 (1H), 6.53 (2H), 6.59 (1H), 6.99 (2H), 7.11 (1H), 7.29(1H), 8.06 (1H), 8.19 (1H), 10.34 (1H), 11.84 (1H)

Example 188N-4-[(6RS)-6-Methyl-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylcarbonyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide

A solution of(6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (141; 45 mg, 108 μmol) and HATU (82 mg, 215 μmol) in DMA (1 mL) wasadded to a mixture of (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptanehydrochloride (44 mg, 323 μmol) and DIPEA (112 μL, 645 μmol) in DMA (1mL) and the reaction was stirred at RT for 3 h. The mixture wasconcentrated and purified by preparative HPLC (basic method) andpreparative TLC (MeOH:DCM) to give the title compound (24 mg, 42%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.37 (3H), 1.53-1.87 (2H), 2.07 (3H),2.38-2.59 (2H), 2.74 (1H), 2.89-3.85 (5H), 4.49-5.12 (2H), 6.50-6.61(3H), 7.00 (2H), 7.15 (1H), 7.36 (1H), 8.08 (1H), 8.21+8.22 (1H),10.35+10.36 (1H), 11.89+11.91 (1H)

Example 189N-4-[(6RS)-6-[(Ethylsulfanyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide

A mixture of[(6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (151-1; 75 mg, 160 μmol) and sodium ethanethiolate (81mg, 960 μmol) in DMA (2.3 mL) was stirred at 100° C. for 5 h. Water wasadded, the mixture concentrated and purified by preparative HPLC (basicmethod) to give the title compound (44 mg, 60%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.19 (3H), 2.07 (3H), 2.26 (1H),2.35-2.47 (2H), 2.54 (2H), 2.59-2.70 (3H), 3.11 (1H), 6.56 (2H), 6.60(1H), 7.01 (2H), 7.14 (1H), 7.34 (1H), 8.06 (1H), 8.24 (1H), 10.32 (1H),11.95 (1H)

Example 190

N-(4-(6RS)-Oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)acetamide

A mixture of[(6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (151-1; 75 mg, 160 μmol) and sodium propane-2-thiolate(94 mg, 960 μmol) in DMA (2.3 mL) was stirred at 100° C. for 5 h. Waterwas added, the mixture concentrated and purified by preparative HPLC(basic method) to give the title compound (43 mg, 57%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.22 (6H), 2.07 (3H), 2.25-2.39 (2H),2.44 (1H), 2.60-2.72 (3H), 2.95 (1H), 3.13 (1H), 6.55 (2H), 6.60 (1H),7.01 (2H), 7.15 (1H), 7.35 (1H), 8.08 (1H), 8.23 (1H), 10.34 (1H), 11.95(1H)

Example 191N-4-[(6RS)-6-[(tert-Butylsulfanyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide

A mixture of[(6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (151-1; 75 mg, 160 μmol) and sodium2-methylpropane-2-thiolate (108 mg, 960 μmol) in DMA (3 mL) was stirredat 1001 for 5 h. Water was added, the mixture concentrated and purifiedby preparative HPLC (basic method) to give the title compound (45 mg,58%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29 (9H), 2.07 (3H), 2.25-2.36 (2H),2.40-2.48 (1H), 2.61-2.71 (3H), 3.11 (1H), 6.55 (2H), 6.60 (1H), 7.01(2H), 7.15 (1H), 7.35 (1H), 8.07 (1H), 8.23 (1H), 10.33 (1H), 11.94 (1H)

Example 192(6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one192-1:[(6RS)-2-(2-Aminopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate

A solution of(6RS)-2-(2-aminopyridin-4-yl)-6-(hydroxymethyl)-3-(phenylamino)-1,5,6,7-tetrahydro-4H-indol-4-one(87; 1.17 g, 3.34 mmol), DMAP (41 mg, 334 μmol) and methanesulfonylchloride (311 μL, 4.01 mmol) in pyridine (18 mL) was stirred at RT for 4h. MeOH was added, the mixture concentrated and purified by Biotage(SNAP silica 110 g, MeOH:DCM) to give the title compound (1.27 g, 89%).

(6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture of[(6RS)-2-(2-aminopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (192-1; 512 mg, 1.20 mmol) and sodiumpropane-2-thiolate (707 mg, 7.20 mmol) in DMA (17 mL) was stirred at100° C. for 5 h. Water was added, the mixture concentrated and purifiedby Biotage (SNAP silica 55 g, MeOH:DCM) to give the title compound (411mg, 84%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.22 (6H), 2.26 (1H), 2.35 (1H), 2.42(1H), 2.59-2.71 (3H), 2.94 (1H), 3.09 (1H), 5.74 (2H), 6.55 (2H), 6.58(1H), 6.60 (1H), 6.69 (1H), 7.02 (2H), 7.22 (1H), 7.76 (1H), 11.71 (1H)

Example 193(6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(S)-propan-2-ylsulfinyl]methyl-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture comprising(6RS)-2-(2-aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one(192; 714 mg, 1.76 mmol), mCPBA (741 mg, 75%) and DMA (50 mL) wasstirred at RT for 16 h. TEA (1 mL) was added, the mixture concentratedand purified by Biotage (SNAP silica 55 g, MeOH:DCM) to give the titlecompound (246 mg, 32%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 (6H), 2.39 (1H), 2.46 (1H),2.63-2.90 (5H), 3.15 (1H), 5.84 (2H), 6.54-6.63 (4H), 6.71 (1H), 7.03(2H), 7.26 (1H), 7.76 (1H), 11.78+11.81 (1H)

Example 194(6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfonAmethyl]-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture comprising(6RS)-2-(2-aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one(192; 714 mg, 1.76 mmol), mCPBA (741 mg, 75%) and DMA (50 mL) wasstirred at RT for 16 h. TEA (1 mL) was added, the mixture concentratedand purified by Biotage (SNAP silica 55 g, MeOH:DCM) to give the titlecompound (173 mg, 21%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.26 (6H), 2.39 (1H), 2.48 (1H),2.76-2.88 (2H), 3.20-3.33 (4H), 5.81 (2H), 6.54-6.63 (4H), 6.71 (1H),7.03 (2H), 7.25 (1H), 7.76 (1H), 11.81 (1H)

Example 195(6RS)-2-2-[(4-Fluorobenzoyl)amino]pyridin-4-yl-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising(6RS)-2-2-[(4-fluorobenzoyl)amino]pyridin-4-yl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (145; 60 mg, 123 μmol), DMF (2 mL), DIPEA (65 μL, 372 μmol),N-methylmethanamine (186 μL, 2M in THF) and T3P (112 μL, 50% in DMF) wasstirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (36 mg, 54%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.33 (1H), 2.53 (1H), 2.86 (3H),2.94-3.03 (2H), 3.07 (3H), 3.65 (1H), 6.59-6.64 (3H), 7.03 (2H), 7.24(1H), 7.36 (2H), 7.41 (1H), 8.10 (2H), 8.18 (1H), 8.34 (1H), 10.74 (1H),12.02 (1H)

Example 196(6RS)-2-2-[(4-Fluorobenzoyl)amino]pyridin-4-yl-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising(6RS)-2-2-[(4-fluorobenzoyl)amino]pyridin-4-yl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (145; 60 mg, 123 μmol), DMF (2 mL), DIPEA (65 μL, 372 μmol),2-(methylamino)ethanol (30 μL, 372 μmol) and T3P (112 μL, 50% in DMF)was stirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (49 mg, 69%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.30-2.38 (1H), 2.46-2.58 (1H),2.86+3.11 (3H), 2.93-3.07 (2H), 3.29-3.56 (4H), 3.60-3.76 (1H),4.69+4.86 (1H), 6.59-6.64 (3H), 7.03 (2H), 7.24 (1H), 7.35 (2H),7.41+7.42 (1H), 8.10 (2H), 8.18 (1H), 8.34 (1H), 10.74 (1H), 12.02 (1H)

Example 197(6RS)—N,N-Dimethyl-4-oxo-3-(phenylamino)-2-2-[(1,3-thiazol-5-ylcarbonyl)amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising(6RS)-4-oxo-3-(phenylamino)-2-2-[(1,3-thiazol-5-ylcarbonyl)amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (146; 60 mg, 127 μmol), DMF (2 mL), DIPEA (66 μL, 380 μmol),N-methylmethanamine (190 μL, 2M in THF) and T3P (114 μL, 50% in DMF) wasstirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (43 mg, 64%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.33 (1H), 2.53 (1H), 2.86 (3H),2.93-3.03 (2H), 3.07 (3H), 3.66 (1H), 6.56-6.64 (3H), 7.03 (2H), 7.25(1H), 7.42 (1H), 8.20 (1H), 8.29 (1H), 8.88 (1H), 9.33 (1H), 11.11 (1H),12.02 (1H)

Example 198(6RS)—N-(2-Hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-2-[(1,3-thiazol-5-ylcarbonyl)amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising(6RS)-4-oxo-3-(phenylamino)-2-2-[(1,3-thiazol-5-ylcarbonyl)amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (146; 60 mg, 127 μmol), DMF (2 mL), DIPEA (66 μL, 380 μmol),2-(methylamino)ethanol (31 μL, 380 μmol) and T3P (114 μL, 50% in DMF)was stirred at RT for 1 h. The mixture was filtered and purified bypreparative HPLC (basic method) to give the title compound (49 mg, 69%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.34 (1H), 2.47-2.56 (1H), 2.86+3.11(3H), 2.89-3.05 (3H), 3.19-3.76 (4H), 3.89 (1H), 6.57-6.64 (3H), 7.03(2H), 7.25 (1H), 7.41+7.42 (1H), 8.19 (1H), 8.29 (1H), 8.88 (1H), 9.33(1H), 11.12 (1H), 12.05 (1H)

Example 199N-{4-[(6RS)-3-Anilino-6-{[(methylsulfonyl)amino]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide

A mixture ofN-4-[(6RS)-6-(aminomethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide(156; 40 mg, 103 μmol), methanesulfonyl chloride (16 μL, 205 μmol) inpyridine (1.2 mL) was stirred at RT for 16 h. MeOH was added, themixture concentrated and purified by preparative TLC (MeOH:DCM) to givethe title compound (36 mg, 70%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.07 (3H), 2.25 (1H), 2.31-2.40 (2H),2.65 (1H), 2.92 (3H), 2.99-3.07 (3H), 6.56 (2H), 6.60 (1H), 7.01 (2H),7.16 (1H), 7.21 (1H), 7.36 (1H), 8.08 (1H), 8.23 (1H), 10.35 (1H), 11.97(1H)

Example 200N-{4-[(6RS)-6-(Acetamidomethyl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide

A mixture ofN-4-[(6RS)-6-(aminomethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide(156; 40 mg, 103 μmol), acetyl chloride (15 μL, 205 μmol) in pyridine(1.2 mL) was stirred at RT for 16 h. MeOH was added, the mixtureconcentrated and purified by preparative TLC (MeOH:DCM) to give thetitle compound (28 mg, 59%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.85 (3H), 2.07 (3H), 2.22 (1H),2.27-2.36 (2H), 2.59 (1H), 2.93 (1H), 3.10 (1H), 3.18 (1H), 6.55 (2H),6.60 (1H), 7.01 (2H), 7.15 (1H), 7.35 (1H), 8.00 (1H), 8.08 (1H), 8.22(1H), 10.34 (1H), 11.95 (1H)

Example 2025-[(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-yl]pentanoicacid

A mixture comprising(4E)-5-[(6RS)-2-[2-(acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-yl]pent-4-enoicacid (149; 27 mg, 59 μmol), Pd/C (6.3 mg, 10%), THF (1 mL) and EtOH (1.3mL) was stirred under an atmosphere of hydrogen at RT for 16 h. Afterfiltration the mixture was concentrated and purified by preparative TLC(MeOH:DCM) to give the title compound (9 mg, 32%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29-1.45 (4H), 1.50 (2H), 2.06 (3H),2.18 (4H), 2.31 (1H), 2.54 (1H), 2.97 (1H), 6.55 (2H), 6.60 (1H), 7.01(2H), 7.15 (1H), 7.35 (1H), 8.07 (1H), 8.22 (1H), 10.34 (1H), 11.93 (1H)

Example 203(6RS)-3-Anilino-N,N-dlisopropyl-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A solution of(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (9; 60 mg, 173 μmol) and HATU (66 mg, 173 μmol) in DMA (1 mL) wasadded to a mixture of N-isopropylpropan-2-amine (73 μL, 518 μmol) andDIPEA (30 μL, 173 μmol) in DMA (1 mL) and the reaction was stirred at50° C. for 16 h. The mixture was concentrated and purified bypreparative HPLC (basic method) to give the title compound (16 mg, 22%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17 (6H), 1.30 (6H), 2.24 (1H), 2.57(1H), 2.90 (1H), 3.03 (1H), 3.42-3.61 (2H), 4.14 (1H), 6.59 (2H), 6.64(1H), 7.08 (2H), 7.43 (1H), 7.46 (2H), 8.42 (2H), 11.93 (1H)

Example 204(6RS)-3-Anilino-2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-N,N-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising of(6RS)-2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (166; 30 mg, 70 μmol), DMF (1.1 mL), DIPEA (55 μL, 316 μmol),N-methylmethanamine (158 μL, 2M in THF) and T3P (95 μL, 50% in DMF) wasstirred at RT for 2 h. The mixture was concentrated and purified bypreparative HPLC (basic method) to give the title compound (5 mg, 16%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.32 (1H), 2.47-2.52 (1H), 2.84 (3H),2.93 (1H), 2.99 (1H), 3.06 (3H), 3.66 (1H), 4.30 (2H), 6.30 (1H), 6.52(2H), 6.55 (1H), 6.94 (2H), 7.28 (1H), 7.42 (1H), 8.11 (1H), 8.35 (1H),11.34 (1H)

Example 205(6RS)-3-Anilino-2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-N-(2-hydroxyethyl)-N-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising of(6RS)-2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (166; 30 mg, 70 μmol), DMF (0.8 mL), DIPEA (37 μL, 211 μmol),2-(methylamino)ethanol (17 μL, 211 μmol) and T3P (63 μL, 50% in DMF) wasstirred at RT for 1 h. The mixture was concentrated and purified bypreparative HPLC (basic method) to give the title compound (10 mg, 29%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.32 (1H), 2.45-2.57 (1H), 2.84+3.10(3H), 2.92 (1H), 3.00 (1H), 3.30-3.54 (4H), 3.64+3.72 (1H), 4.29 (2H),4.67+4.83 (1H), 6.30 (1H), 6.51 (2H), 6.55 (1H), 6.95 (2H), 7.28 (1H),7.42+7.43 (1H), 8.11 (1H), 8.35 (1H), 11.33+11.35 (1H)

Example 206(6RS)-3-Anilino-2-[3-(2-hydroxyethoxy)pyridin-4-yl]-N,N-dimethyl-4-oxo-4,5,6,7-tetrahydro-.1H-indol-6-carboxamide

A mixture comprising of(6RS)-2-[3-(2-hydroxyethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (165; 50 mg, 123 μmol), DMF (1.8 mL), DIPEA (64 μL, 368 μmol),N-methylmethanamine (184 μL, 2M in THF) and T3P (114 μL, 50% in DMF) wasstirred at RT for 1 h. The mixture was concentrated and purified bypreparative HPLC (basic method) to give the title compound (8 mg, 14%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.34 (1H), 2.52 (1H), 2.87 (3H), 2.94(1H), 3.00 (1H), 3.08 (3H), 3.68 (1H), 3.86 (2H), 4.26 (2H), 5.59 (1H),6.59 (2H), 6.61 (1H), 7.01 (2H), 7.32 (1H), 7.43 (1H), 8.02 (1H), 8.42(1H), 11.55 (1H)

Example 207 (6RS)-3-Anilino-2-[3-(2-hydroxyethoxy)pyridin-4-yl]-N-(2-hydroxyethyl)-N-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising of(6RS)-2-[3-(2-hydroxyethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (165; 50 mg, 123 μmol), DMF (1.8 mL), DIPEA (64 μL, 368 μmol),2-(methylamino)ethanol (30 μL, 368 μmol) and T3P (111 μL, 50% in DMF)was stirred at RT for 1 h. The mixture was concentrated and purified bypreparative HPLC (basic method) to give the title compound (12 mg, 19%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.32-2.38 (1H), 2.49-2.59 (1H),2.87+3.12 (3H), 2.93 (1H), 3.01 (1H), 3.29-3.55 (4H), 3.66+3.73 (1H),3.85 (2H), 4.21-4.30 (2H), 4.67+4.83 (1H), 5.57 (1H), 6.56-6.63 (3H),7.01 (2H), 7.33 (1H), 7.42+7.44 (1H), 8.02+8.03 (1H), 8.42 (1H), 11.55(1H)

Example 208(6RS)-3-Anilino-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-N,N-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A mixture comprising of(6RS)-3-anilino-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (158; 30 mg, 72 μmol), DMF (1.1 mL), DIPEA (38 μL, 216 μmol),N-methylmethanamine (108 μL, 2M in THF) and T3P (65 μL, 50% in DMF) wasstirred at RT for 1 h. The mixture was concentrated and purified bypreparative HPLC (basic method) to give the title compound (15 mg, 47%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.35 (2H), 0.56 (2H), 1.29 (1H), 2.32(1H), 2.51 (1H), 2.86 (3H), 2.92-3.04 (2H), 3.07 (3H), 3.67 (1H), 3.93(2H), 6.54 (2H), 6.57 (1H), 6.97 (2H), 7.27 (1H), 7.36 (1H), 8.04 (1H),8.31 (1H), 11.30 (1H)

Example 209 Methyl(6RS)-3-anilino-2-[2-({[(1RS)-2,2-difluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate

A solution of methyl(6RS)-2-(2-aminopyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate(31; 150 mg, 398 μmol) and HATU (348 mg, 917 μmol) in DMF (1 mL) wasadded to a mixture of (1RS)-2,2-difluorocyclopropanecarboxylic acid (112mg, 917 μmol) and DIPEA (160 μL, 917 μmol) in DMF (1 mL) and thereaction was stirred at 50° C. for 16 h. The mixture was concentratedand purified by Biotage (SNAP silica 10 g, MeOH:DCM) to give the titlecompound (154 mg, 72%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.01 (2H), 2.53 (1H), 2.58 (1H), 2.98(1H), 3.10 (1H), 3.18 (1H), 3.35 (1H), 3.64 (3H), 6.55 (2H), 6.61 (1H),7.01 (2H), 7.19 (1H), 7.41 (1H), 8.12 (1H), 8.22 (1H), 10.90 (1H), 12.05(1H)

Example 210(6RS)-3-Anilino-2-[2-({[(1RS)-2,2-difluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid

A mixture of methyl(6RS)-3-anilino-2-[2-({[(1RS)-2,2-difluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate(209; 150 mg, 312 μmol), potassium hydroxide (1.25 mL, 4M in water), THF(1.2 mL) and MeOH (1.2 mL) was stirred at RT for 10 minutes.Hydrochloric acid (1.67 mL, 3M) was added and the mixture concentrated.The precipitate was washed with water and dried to give the titlecompound (111 mg, 77%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.91-2.06 (2H), 2.51-2.61 (2H), 2.98(1H), 3.06-3.17 (2H), 3.22 (1H), 6.55 (2H), 6.61 (1H), 7.01 (2H), 7.18(1H), 7.41 (1H), 8.11 (1H), 8.22 (1H), 10.89 (1H), 12.02 (1H), 12.59(1H)

Example 211(6RS)-3-Anilino-2-[2-({[(1RS)-2,2-difluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N,N-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-le-6-carboxamide

A mixture comprising of (6RS)-3-Anilino-2-[2-({[(1RS)-2,2-difluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (210; 55 mg, 118 μmol), DMF (1.5 mL), DIPEA (62 μL, 354 μmol),N-methylmethanamine (177 μL, 2M in THF) and T3P (106 μL, 50% in DMF) wasstirred at RT for 1 h. The mixture was concentrated and purified bypreparative HPLC (basic method) to give the title compound (24 mg, 39%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.01 (2H), 2.33 (1H), 2.48-2.56 (1H),2.86 (3H), 2.94-3.04 (2H), 3.07 (3H), 3.33 (1H), 3.65 (1H), 6.59 (2H),6.63 (1H), 7.03 (2H), 7.19 (1H), 7.37 (1H), 8.12 (1H), 8.23 (1H), 10.87(1H), 11.97 (1H)

Example 212N-(4-{(6RS)-3-Anilino-6-[(isopropylsulfanyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)-4-fluoro-3-methoxybenzamide

A solution of 4-fluoro-3-methoxybenzoic acid (42 mg, 246 μmol) and HATU(94 mg, 246 μmol) in DMA (1.2 mL) was added to a mixture of(6RS)-2-(2-aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one(192; 50 mg, 123 μmol) and DIPEA (43 μL, 246 μmol) in DMA (1.2 mL) andthe reaction was stirred at 50° C. for 16 h. The mixture wasconcentrated and purified by preparative HPLC (basic method) andcrystallization from MeOH to give the title compound (18 mg, 25%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21 (6H), 2.29 (1H), 2.37 (1H), 2.44(1H), 2.61-2.71 (3H), 2.94 (1H), 3.13 (1H), 3.93 (3H), 6.57 (2H), 6.60(1H), 7.01 (2H), 7.23 (1H), 7.35 (1H), 7.39 (1H), 7.63 (1H), 7.84 (1H),8.17 (1H), 8.34 (1H), 10.77 (1H), 12.00 (1H)

Example 213N-(4-{(6RS)-3-Anilino-6-[(isopropylsulfanyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)-2-fluoro-2-methylpropanamide

A solution of 2-fluoro-2-methylpropanoic acid (26 mg, 246 μmol) and HATU(94 mg, 246 μmol) in DMA (1.2 mL) was added to a mixture of(6RS)-2-(2-aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one(192; 50 mg, 123 μmol) and DIPEA (43 μL, 246 μmol) in DMA (1.2 mL) andthe reaction was stirred at 50° C. for 16 h. The mixture wasconcentrated and purified by preparative HPLC (basic method) andcrystallization from MeOH to give the title compound (17 mg, 27%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21 (6H), 1.54 (3H), 1.58 (3H), 2.28(1H), 2.36 (1H), 2.44 (1H), 2.59-2.70 (3H), 2.93 (1H), 3.12 (1H), 6.55(2H), 6.60 (1H), 7.01 (2H), 7.22 (1H), 7.40 (1H), 8.11-8.14 (2H), 9.70(1H), 11.98 (1H)

Example 2141-(4-{(6RS)-3-Anilino-6-[(isopropylsulfanyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)-3-cyclopropylurea

A mixture of(6RS)-2-(2-aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one(192; 60 mg, 148 μmol), isocyanatocyclopropane (25 μL, 295 μmol) inpyridine (1.6 mL) was stirred at RT for 2.5 days. The mixture wasconcentrated and purified by preparative TLC (MeOH:DCM) andcrystallization from MeOH to give the title compound (10 mg, 13%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.41 (2H), 0.64 (2H), 1.20 (6H), 2.27(1H), 2.34 (1H), 2.43 (1H), 2.56 (1H), 2.60-2.69 (3H), 2.93 (1H), 3.10(1H), 6.54 (2H), 6.59 (1H), 6.98-7.03 (3H), 7.31 (1H), 7.53 (1H), 7.95(1H), 8.03 (1H), 8.98 (1H), 11.87 (1H)

Example 2151-(4-{(6RS)-3-Anilino-6-[(isopropylsulfonyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)-3-cyclopropylurea

A mixture of(6RS)-2-(2-aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one(194; 30 mg, 68 μmol), isocyanatocyclopropane (11 μL, 137 μmol) inpyridine (0.8 mL) was stirred at RT for 16 h. The mixture wasconcentrated and purified by crystallization from MeOH to give the titlecompound (21 mg, 55%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.41 (2H), 0.64 (2H), 1.25 (6H), 2.39(1H), 2.50 (1H), 2.56 (1H), 2.76-2.86 (2H), 3.22-3.31 (4H), 6.54 (2H),6.59 (1H), 7.00 (2H), 7.02 (1H), 7.32 (1H), 7.54 (1H), 7.96 (1H), 8.03(1H), 8.99 (1H), 11.96 (1H)

Example 216N-{[(6RS)-3-Anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl}-L-alaninamide

A mixture comprising tert-butyl[(2S)-1-oxo-1-([(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylamino)propan-2-yl]carbamate(89; 54 mg, 107 μmol), TFA (124 μL, 1.61 mmol) and DCM (3.5 mL) wasstirred at RT for 16 h. Ammonia (0.5 mL, 25% in water) and DMSO (3 mL)were added, the mixture concentrated and purified by preparative HPLC(basic method) to give the title compound (36 mg, 79%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17 (3H), 2.24 (1H), 2.31 (1H), 2.38(1H), 2.62 (1H), 2.72 (1H), 2.92 (1H), 3.13-3.27 (2H), 3.32 (1H), 6.57(2H), 6.63 (1H), 7.04 (2H), 7.43 (1H), 7.47 (2H), 8.02 (1H), 8.41 (2H),11.93 (1H)

Example 217(6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N,N,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide217-2: Methyl(6RS)-3-anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate

A solution of (1S,2S)-2-fluorocyclopropanecarboxylic acid (373 mg, 3.59mmol) and HATU (1.36 g, 3.59 mmol) in DMF (13 mL) was added to a mixtureof methyl(6RS)-2-(2-aminopyridin-4-yl)-3-anilino-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate(141-2; 700 mg, 1.79 mmol) and DIPEA (625 μL, 3.59 mmol) in DMF (13 mL)and the reaction was stirred at RT for 2.5 days. The mixture wasconcentrated and EtOAc was added. The mixture was washed with water,brine and dried over sodium sulfate. After filtration and removal of thesolvent, the title compound (578 mg, 64%) was used without furtherpurification.

217-1:(6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid

A mixture of methyl(6RS)-3-anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate(217-2; 574 mg, 1.21 mmol), lithium hydroxide (7.2 mL, 1M in water), THF(21 mL) and MeOH (6.7 mL) was stirred at RT for 16 h. and at 50° C. for3 h. Citric acid (486 mg) in water (10 mL) was added and the mixtureconcentrated. The precipitate was washed with water and dried to givethe title compound (425 mg, 72%).

(6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N,N,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A solution of(6RS)-3-Anilino-2-[2-({[(1S,23)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (217-1; 47 mg, 102 μmol) and HATU (77 mg, 203 μmol) in DMA (0.9 mL)was added to a mixture of N-methylmethanamine (152 μL, 2M in THF) andDIPEA (53 μL, 305 μmol) in DMA (0.9 mL) and the reaction was stirred atRT for 16 h. The mixture was concentrated and purified by preparativeTLC (MeOH:DCM) to give the title compound (25 mg, 48%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 (1H), 1.40 (3H), 1.64 (1H), 2.20(1H), 2.44 (1H), 2.77 (1H), 2.91 (1H), 2.94 (6H), 3.51 (1H), 4.93 (1H),6.53 (2H), 6.59 (1H), 7.01 (2H), 7.14 (1H), 7.37 (1H), 8.07 (1H), 8.24(1H), 10.72 (1H), 11.89 (1H)

Example 218(6RS)-3-Anilino-N,N-diethyl-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A solution of(6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (217-1; 47 mg, 102 μmol) and HATU (77 mg, 203 μmol) in DMA (0.9 mL)was added to a mixture of N-ethylethanaminium chloride (33 mg, 305 μmol)and DIPEA (106 μL, 610 μmol) in DMA (0.9 mL) and the reaction wasstirred at RT for 16 h. The mixture was concentrated and purified bypreparative TLC (MeOH:DCM) to give the title compound (22 mg, 40%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.01 (6H), 1.18 (1H), 1.39 (3H), 1.64(1H), 2.20 (1H), 2.44 (1H), 2.72 (1H), 2.91 (1H), 3.30 (4H), 3.42 (1H),4.93 (1H), 6.53 (2H), 6.59 (1H), 6.99 (2H), 7.15 (1H), 7.35 (1H), 8.07(1H), 8.23 (1H), 10.72 (1H), 11.90 (1H)

Example 219(6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N,6-dimethyl-4-oxo-N-propyl-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A solution of(6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (217-1; 47 mg, 102 μmol) and HATU (77 mg, 203 μmol) in DMA (0.9 mL)was added to a mixture of N-methylpropan-1-amine (31 μL, 305 μmol) andDIPEA (53 μL, 305 μmol) in DMA (0.9 mL) and the reaction was stirred atRT for 16 h. The mixture was concentrated and purified by preparativeTLC (MeOH:DCM) to give the title compound (16 mg, 29%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.69 (3H), 1.18 (1H), 1.37 (2H), 1.40(3H), 1.64 (1H), 2.20 (1H), 2.42 (1H), 2.75 (1H), 2.91 (1H), 2.95-3.17(4H), 3.29 (1H), 3.51 (1H), 4.93 (1H), 6.53 (2H), 6.59 (1H), 7.00 (2H),7.13 (1H), 7.34 (1H), 8.07 (1H), 8.23 (1H), 10.72 (1H), 11.88 (1H)

Example 220(6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N-isobutyl-N,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A solution of(6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (217-1; 47 mg, 102 μmol) and HATU (77 mg, 203 μmol) in DMA (0.9 mL)was added to a mixture of N,2-dimethylpropan-1-amine (37 μL, 305 μmol)and DIPEA (53 μL, 305 μmol) in DMA (0.9 mL) and the reaction was stirredat RT for 16 h. The mixture was concentrated and purified by preparativeTLC (MeOH:DCM) to give the title compound (16 mg, 27%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.55 (3H), 0.67 (3H), 1.18 (1H), 1.41(3H), 1.58-1.77 (2H), 2.20 (1H), 2.38 (1H), 2.76 (1H), 2.82 (1H), 2.93(1H), 3.10 (3H), 3.26 (1H), 3.57 (1H), 4.93 (1H), 6.53 (2H), 6.59 (1H),6.99 (2H), 7.11 (1H), 7.31 (1H), 8.06 (1H), 8.22 (1H), 10.71 (1H), 11.86(1H)

Example 221(6RS)-3-Anilino-N-(cyclopropylmethyl)-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A solution of(6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (217-1; 47 mg, 102 μmol) and HATU (77 mg, 203 μmol) in DMA (0.9 mL)was added to a mixture of cyclopropyl-N-methylmethanaminium chloride (37mg, 305 μmol) and DIPEA (106 μL, 610 μmol) in DMA (0.9 mL) and thereaction was stirred at RT for 16 h. The mixture was concentrated andpurified by preparative TLC (MeOH:DCM) to give the title compound (12mg, 21%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.05 (1H), 0.13 (1H), 0.30 (1H), 0.36(1H), 0.81 (1H), 1.18 (1H), 1.41 (3H), 1.64 (1H), 2.20 (1H), 2.42 (1H),2.77 (1H), 2.92 (1H), 3.01-3.12 (4H), 3.25 (1H), 3.53 (1H), 4.93 (1H),6.53 (2H), 6.59 (1H), 6.99 (2H), 7.13 (1H), 7.35 (1H), 8.07 (1H), 8.23(1H), 10.72 (1H), 11.89 (1H)

Example 222(6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N,6-dimethyl-4-oxo-N-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A solution of(6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (217-1; 47 mg, 102 μmol) and HATU (77 mg, 203 μmol) in DMA (0.9 mL)was added to a mixture of 3,3,3-trifluoro-N-methylpropan-1-aminiumchloride (50 mg, 305 μmol) and DIPEA (106 μL, 610 μmol) in DMA (0.9 mL)and the reaction was stirred at RT for 16 h. The mixture wasconcentrated and purified by preparative TLC (MeOH:DCM) to give thetitle compound (30 mg, 49%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 (1H), 1.39 (3H), 1.64 (1H), 2.20(1H), 2.27-2.39 (2H), 2.43 (1H), 2.75 (1H), 2.94 (1H), 3.13 (3H), 3.32(1H), 3.44-3.55 (2H), 4.93 (1H), 6.53 (2H), 6.59 (1H), 6.99 (2H), 7.15(1H), 7.34 (1H), 8.07 (1H), 8.24 (1H), 10.72 (1H), 11.89 (1H)

Example 223(1S,2S)—N-{4-[(6RS)-3-Anilino-6-methyl-4-oxo-6-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}-2-fluorocyclopropanecarboxamide

A solution of(6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (217-1; 47 mg, 102 μmol) and HATU (77 mg, 203 μmol) in DMA (0.9 mL)was added to a mixture of pyrrolidine (25 μL, 305 μmol) and DIPEA (53μL, 305 μmol) in DMA (0.9 mL) and the reaction was stirred at RT for 16h. The mixture was concentrated and purified by preparative TLC(MeOH:DCM) to give the title compound (26 mg, 46%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 (1H), 1.33 (3H), 1.64 (1H), 1.78(4H), 2.20 (1H), 2.47 (1H), 2.80 (1H), 2.86 (1H), 3.10-3.81 (5H), 4.93(1H), 6.53 (2H), 6.59 (1H), 7.00 (2H), 7.15 (1H), 7.38 (1H), 8.08 (1H),8.24 (1H), 10.72 (1H), 11.90 (1H)

Example 224(1S,2S)—N-{4-[(6RS)-3-Anilino-6-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}-2-fluorocyclopropanecarboxamide

A solution of(6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (217-1; 47 mg, 102 μmol) and HATU (77 mg, 203 μmol) in DMA (0.9 mL)was added to a mixture of (3R)—N,N-dimethylpyrrolidin-3-amine (39 μL,305 μmol) and DIPEA (53 μL, 305 μmol) in DMA (0.9 mL) and the reactionwas stirred at RT for 16 h. The mixture was concentrated and purified bypreparative TLC (MeOH:DCM) to give the title compound (18 mg, 30%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 (1H), 1.34 (3H), 1.46-1.80 (2H),1.83-2.25 (2H), 2.15 (6H), 2.41 (1H), 2.77 (1H), 2.92 (1H), 2.98-3.99(6H), 4.93 (1H), 6.54 (2H), 6.59 (1H), 7.00 (2H), 7.14 (1H), 7.38 (1H),8.08 (1H), 8.24 (1H), 10.73 (1H), 11.89 (1H)

Example 225(1S,2S)—N-{4-[(6RS)-3-Anilino-6-methyl-4-oxo-6-(piperidin-1-ylcarbonyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}-2-fluorocyclopropanecarboxamide

A solution of(6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (217-1; 47 mg, 102 μmol) and HATU (77 mg, 203 μmol) in DMA (0.9 mL)was added to a mixture of piperidine (30 μL, 305 μmol) and DIPEA (53 μL,305 μmol) in DMA (0.9 mL) and the reaction was stirred at RT for 16 h.The mixture was concentrated and purified by preparative TLC (MeOH:DCM)to give the title compound (31 mg, 55%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 (1H), 1.40 (3H), 1.44 (4H),1.53-1.70 (3H), 2.20 (1H), 2.44 (1H), 2.73 (1H), 2.93 (1H), 3.39-3.53(5H), 4.93 (1H), 6.53 (2H), 6.59 (1H), 7.00 (2H), 7.14 (1H), 7.36 (1H),8.07 (1H), 8.24 (1H), 10.72 (1H), 11.90 (1H)

Example 226N-{4-[(6RS)-3-Anilino-6-({[2-(dimethylamino)ethyl]sulfanyl}methyl)-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide

A mixture of[(6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (151-1; 75 mg, 160 μmol) and sodium2-(dimethylamino)ethanethiolate (122 mg, 960 μmol) in DMA (3 mL) wasstirred at 1001 for 5 h. Water was added, the mixture concentrated andpurified by preparative HPLC (basic method) and preparative TLC(MeOH:DCM) to give the title compound (7 mg, 9%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.07 (3H), 2.14 (6H), 2.27 (1H),2.35-2.49 (4H), 2.59-2.71 (5H), 3.13 (1H), 6.56 (2H), 6.60 (1H), 7.01(2H), 7.15 (1H), 7.35 (1H), 8.08 (1H), 8.23 (1H), 10.34 (1H), 11.95 (1H)

Example 227N-(4-{(6RS)-3-Anilino-6-[(isopropylsulfonyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)-4-fluoro-N-methylbenzamide

A mixture of(6RS)-2-(2-aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one(194; 30 mg, 68 μmol) and (4-fluorophenyl)methylcarbamic chloride (26mg, 137 μmol) in pyridine (0.8 mL) was stirred at RT for 16 h. Themixture was concentrated and purified by preparative TLC (MeOH:DCM) togive the title compound (9 mg, 21%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.26 (6H), 2.41 (1H), 2.53 (1H),2.75-2.89 (2H), 3.23-3.32 (4H), 3.26 (3H), 6.57 (2H), 6.62 (1H), 7.03(2H), 7.10 (1H), 7.29 (2H), 7.36 (1H), 7.41 (2H), 7.92 (1H), 7.95 (1H),8.04 (1H), 12.03 (1H)

Example 228(6RS)-2-(2-Aminopyridin-4-yl)-6-(hydroxymethyl)-6-methyl-3-(phenylamino)-1,5,6,7-tetrahydro-4H-indol-4-one228-2:(4RS)-2-{[(2-Aminopyridin-4-yl)methyl]amino}-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-6-oxo-N-phenylcyclohex-1-ene-1-carbothioamide

A solution of(4RS)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-6-oxo-N-phenyl-2-[(pyridin-4-ylmethyl)amino]cyclohex-1-ene-1-carbothioamide(30-3; 9.9 g, 18.7 mmol) and 4-(aminomethyl)pyridin-2-amine (4.14 g,33.6 mmol) in DMA (52 mL) was heated at 90-100° C. for 10 h. The mixturewas poured into water, extracted with EtOAc, washed with brine and driedover sodium sulfate. After filtration the mixture was concentrated andpurified by Biotage (SNAP silica 340 g, EtOAc:Hexane) to give the titlecompound (6.07 g, 51%).

228-1:(6RS)-2-(2-Aminopyridin-4-yl)-3-anilino-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-methyl-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture of(4RS)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-6-oxo-N-phenyl-2-[(pyridin-4-ylmethyl)amino]cyclohex-1-ene-1-carbothioamide(228-2; 27.9 g, 43.9 mmol), hydrogen peroxide (30% in water, 17.9 mL,176 mmol) in MeOH (836 mL) was heated at 50° C. for 16 h. The mixturewas concentrated and purified by Biotage (SNAP silica 340 g,EtOAc:Hexane) to give the title compound (18.6 g, 71%).

(6RS)-2-(2-Aminopyridin-4-yl)-6-(hydroxymethyl)-6-methyl-3-(phenylamino)-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture of(6RS)-2-(2-aminopyridin-4-yl)-3-anilino-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-methyl-1,5,6,7-tetrahydro-4H-indol-4-one(228-1; 1.5 g, 2.5 mmol) and TBAF (6.2 mL, 1M in THF) in THF (35 mL) wasstirred at 50° C. for 16 h. EtOAc (100 mL) was added, the mixture washedwith sodium hydroxide (2.5% in water), brine and dried over sodiumsulfate. After filtration and removal of the solvent the residue waspurified by Biotage (SNAP silica 340 g, MeOH:DCM) to give the titlecompound (540 mg, 57%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.98 (3H), 2.06 (1H), 2.37 (1H), 2.56(1H), 2.93 (1H), 3.24 (1H), 3.29 (1H), 4.85 (1H), 5.73 (2H), 6.56 (2H),6.60 (1H), 6.61 (1H), 6.71 (1H), 7.03 (2H), 7.22 (1H), 7.77 (1H), 11.65(1H)

Example 229N-4-[(6RS)-6-[(2-Methoxyethyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide

A mixture of[(6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (151-1; 75 mg, 160 μmol) and sodium2-methoxyethanethiolate (110 mg, 960 μmol) in DMA (3 mL) was stirred at100° C. for 5 h. Water was added, the mixture concentrated and purifiedby preparative HPLC (basic method) to give the title compound (54 mg,72%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.08 (3H), 2.28 (1H), 2.40 (1H), 2.45(1H), 2.62-2.73 (5H), 3.14 (1H), 3.26 (3H), 3.50 (2H), 6.57 (2H), 6.61(1H), 7.02 (2H), 7.16 (1H), 7.34 (1H), 8.09 (1H), 8.23 (1H), 10.32 (1H),11.94 (1H)

Example 230N-4-[(6RS)-6-[(1,3-Oxazol-2-ylsulfanyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide

A mixture of[(6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (151-1; 75 mg, 160 μmol) and sodium1,3-oxazole-2-thiolate (118 mg, 960 μmol) in DMA (3 mL) was stirred at100° C. for 5 h. Water was added, the mixture concentrated and purifiedby preparative HPLC (basic method) to give the title compound (54 mg,68%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.08 (3H), 2.37 (1H), 2.45 (1H), 2.59(1H), 2.74 (1H), 3.13 (1H), 3.29-3.41 (2H), 6.56 (2H), 6.61 (1H), 7.02(2H), 7.16 (1H), 7.27 (1H), 7.33 (1H), 8.09 (1H), 8.17 (1H), 8.23 (1H),10.32 (1H), 11.96 (1H)

Example 231N-(4-(6RS)-Oxo-3-(phenylamino)-6-[(1,3-thiazol-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)acetamide

A mixture of[(6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (151-1; 75 mg, 160 μmol) and sodium1,3-thiazole-2-thiolate (134 mg, 960 μmol) in DMA (3 mL) was stirred at100° C. for 5 h. Water was added, the mixture concentrated and purifiedby preparative HPLC (basic method) to give the title compound (53 mg,64%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.08 (3H), 2.39 (1H), 2.47 (1H), 2.60(1H), 2.77 (1H), 3.15 (1H), 3.42 (2H), 6.57 (2H), 6.61 (1H), 7.02 (2H),7.16 (1H), 7.33 (1H), 7.68 (1H), 7.75 (1H), 8.09 (1H), 8.23 (1H), 10.32(1H), 11.95 (1H)

Example 232N-(4-(6RS)-Oxo-3-(phenylamino)-6-[(pyridin-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)acetamide

A mixture of[(6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (151-1; 75 mg, 160 μmol) and sodium pyridine-2-thiolate(128 mg, 960 μmol) in DMA (3 mL) was stirred at 1000 for 5 h. Water wasadded, the mixture concentrated and purified by preparative HPLC (basicmethod) to give the title compound (54 mg, 66%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.07 (3H), 2.36 (1H), 2.47 (1H), 2.50(1H), 2.73 (1H), 3.12 (1H), 3.28-3.40 (2H), 6.56 (2H), 6.60 (1H), 7.01(2H), 7.09-7.18 (2H), 7.32 (1H), 7.36 (1H), 7.65 (1H), 8.06 (1H), 8.23(1H), 8.44 (1H), 10.29 (1H), 11.92 (1H)

Example 233N-4-[(6RS)-6-[(4-Fluorobenzyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide

A mixture of[(6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (151-1; 75 mg, 160 μmol) and sodium(4-fluorophenyl)methanethiolate (158 mg, 960 μmol) in DMA (3 mL) wasstirred at 100° C. for 5 h. Water was added, the mixture concentratedand purified by preparative HPLC (basic method) to give the titlecompound (64 mg, 74%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.08 (3H), 2.23 (1H), 2.36-2.44 (2H),2.56 (1H), 2.63 (1H), 3.09 (1H), 3.35 (1H), 3.78 (2H), 6.57 (2H), 6.61(1H), 7.02 (2H), 7.12-7.17 (3H), 7.33 (1H), 7.38 (2H), 8.06 (1H), 8.25(1H), 10.29 (1H), 11.93 (1H)

Example 234(15,25)-2-Fluoro-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)cyclopropanecarboxamide

A solution of (1S,2S)-2-fluorocyclopropanecarboxylic acid (26 mg, 246μmol) and HATU (94 mg, 246 μmol) in DMA (1.2 mL) was added to a mixtureof(6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one(192; 50 mg, 123 μmol) and DIPEA (43 μL, 246 μmol) in DMA (1.2 mL) andthe reaction was stirred at 50° C. for 16 h. The mixture wasconcentrated and purified by preparative HPLC (basic method) andpreparative TLC (MeOH:DCM) to give the title compound (24 mg, 38%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.16 (1H), 1.20 (6H), 1.62 (1H), 2.18(1H), 2.27 (1H), 2.34 (1H), 2.43 (1H), 2.58-2.70 (3H), 2.93 (1H), 3.12(1H), 4.90 (1H), 6.54 (2H), 6.59 (1H), 7.00 (2H), 7.14 (1H), 7.35 (1H),8.07 (1H), 8.24 (1H), 10.70 (1H), 11.97 (1H)

Example 235N-(4-(6RS)-Oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)-1,3-thiazole-5-carboxamide

A solution of 1,3-thiazole-5-carboxylic acid (32 mg, 246 μmol) and HATU(94 mg, 246 μmol) in DMA (1.2 mL) was added to a mixture of(6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one(192; 50 mg, 123 μmol) and DIPEA (43 μL, 246 μmol) in DMA (1.2 mL) andthe reaction was stirred at 50° C. for 16 h. The mixture wasconcentrated and purified by preparative HPLC (basic method) andpreparative TLC (MeOH:DCM) to give the title compound (30 mg, 45%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21 (6H), 2.29 (1H), 2.36 (1H), 2.44(1H), 2.60-2.71 (3H), 2.93 (1H), 3.13 (1H), 6.57 (2H), 6.60 (1H), 7.01(2H), 7.24 (1H), 7.40 (1H), 8.18 (1H), 8.28 (1H), 8.86 (1H), 9.31 (1H),11.08 (1H), 12.00 (1H)

Example 2364-Fluoro-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)benzamide

A solution of 4-fluorobenzoic acid (34 mg, 246 μmol) and HATU (94 mg,246 μmol) in DMA (1.2 mL) was added to a mixture of(6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one(192; 50 mg, 123 μmol) and DIPEA (43 μL, 246 μmol) in DMA (1.2 mL) andthe reaction was stirred at 50° C. for 16 h. The mixture wasconcentrated and purified by preparative HPLC (basic method) andpreparative TLC (MeOH:DCM) to give the title compound (24 mg, 34%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21 (6H), 2.29 (1H), 2.37 (1H), 2.45(1H), 2.60-2.71 (3H), 2.94 (1H), 3.13 (1H), 6.57 (2H), 6.59 (1H), 7.01(2H), 7.23 (1H), 7.34 (2H), 7.39 (1H), 8.08 (2H), 8.16 (1H), 8.32 (1H),10.72 (1H), 11.99 (1H)

Example 2374-Chloro-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)benzamide

A solution of 4-chlorobenzoic acid (39 mg, 246 μmol) and HATU (94 mg,246 μmol) in DMA (1.2 mL) was added to a mixture of(6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one(192; 50 mg, 123 μmol) and DIPEA (43 μL, 246 μmol) in DMA (1.2 mL) andthe reaction was stirred at 50° C. for 16 h. The mixture wasconcentrated and purified by preparative HPLC (basic method) andpreparative TLC (MeOH:DCM) to give the title compound (26 mg, 37%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21 (6H), 2.29 (1H), 2.36 (1H), 2.44(1H), 2.60-2.71 (3H), 2.94 (1H), 3.13 (1H), 6.57 (2H), 6.59 (1H), 7.01(2H), 7.23 (1H), 7.40 (1H), 7.58 (2H), 8.02 (2H), 8.16 (1H), 8.32 (1H),10.78 (1H), 12.00 (1H)

Example 2383,4-Dichloro-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)benzamide

A solution of 3,4-dichlorobenzoic acid (39 mg, 246 μmol) and HATU (94mg, 246 μmol) in DMA (1.2 mL) was added to a mixture of(6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one(192; 50 mg, 123 μmol) and DIPEA (43 μL, 246 μmol) in DMA (1.2 mL) andthe reaction was stirred at 50° C. for 16 h. The mixture wasconcentrated and purified by preparative HPLC (basic method) andpreparative TLC (MeOH:DCM) to give the title compound (26 mg, 37%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21 (6H), 2.29 (1H), 2.37 (1H), 2.44(1H), 2.59-2.71 (3H), 2.94 (1H), 3.13 (1H), 6.57 (2H), 6.60 (1H), 7.01(2H), 7.24 (1H), 7.40 (1H), 7.79 (1H), 7.96 (1H), 8.18 (1H), 8.25 (1H),8.31 (1H), 10.91 (1H), 12.00 (1H)

Example 239N-4-[(6RS)-6-[(Ethylsulfonyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide

A mixture comprisingN-4-[(6RS)-6-[(ethylsulfanyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide(189; 37 mg, 85 μmol), mCPBA (36 mg, 75%) and DMA (2.5 mL) was stirredat RT. After 16 h a second portion mCPBA (9 mg, 75%) was added. Themixture was stirred at RT for 4 h, DMSO (750 μL) was added, the mixtureconcentrated and purified by preparative HPLC (basic method) to give thetitle compound (23 mg, 58%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.25 (3H), 2.08 (3H), 2.41 (1H),2.48-2.57 (2H), 2.81-2.89 (2H), 3.16 (2H), 3.25-3.31 (2H), 6.58 (2H),6.62 (1H), 7.03 (2H), 7.18 (1H), 7.35 (1H), 8.09 (1H), 8.24 (1H), 10.32(1H), 12.01 (1H)

Example 240N-(4-(6RS)-Oxo-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)acetamide

A mixture comprisingN-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)acetamide(190; 36 mg, 80 μmol), mCPBA (34 mg, 75%) and DMA (2.5 mL) was stirredat RT. After 16 h a second portion mCPBA (8 mg, 75%) was added. Themixture was stirred at RT for 4 h, DMSO (750 μL) was added, the mixtureconcentrated and purified by preparative HPLC (basic method) to give thetitle compound (23 mg, 57%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.25 (6H), 2.05 (3H), 2.39 (1H), 2.51(1H), 2.77-2.86 (2H), 3.23-3.31 (4H), 6.55 (2H), 6.59 (1H), 7.00 (2H),7.15 (1H), 7.34 (1H), 8.07 (1H), 8.22 (1H), 10.33 (1H), 12.01 (1H)

Example 2412-Fluoro-2-methyl-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)propanamide

A mixture comprisingN-(4-{(6RS)-3-anilino-6-[(isopropylsulfanyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)-2-fluoro-2-methylpropanamide(213; 28 mg, 57 μmol), mCPBA (30 mg, 75%) and DMA (2 mL) was stirred atRT for 16 h. The mixture was concentrated and purified by preparativeHPLC (basic method) to give the title compound (18 mg, 58%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.28 (6H), 1.57 (3H), 1.61 (3H), 2.44(1H), 2.49-2.57 (2H), 2.81-2.90 (2H), 3.26-3.38 (3H), 6.59 (2H), 6.63(1H), 7.04 (2H), 7.27 (1H), 7.41 (1H), 8.15 (1H), 8.17 (1H), 9.68 (1H),12.07 (1H)

Example 2424-Fluoro-3-methoxy-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)benzamide

A mixture comprisingN-(4-{(6RS)-3-anilino-6-[(isopropylsulfanyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)-4-fluoro-3-methoxybenzamide(212; 32 mg, 57 μmol), mCPBA (30 mg, 75%) and DMA (2 mL) was stirred atRT for 16 h. The mixture was concentrated and purified by preparativeHPLC (basic method) to give the title compound (16 mg, 44%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.28 (6H), 2.44 (1H), 2.48-2.58 (2H),2.81-2.92 (2H), 3.27-3.35 (3H), 3.96 (3H), 6.61 (2H), 6.63 (1H), 7.04(2H), 7.27 (1H), 7.37 (1H), 7.41 (1H), 7.66 (1H), 7.86 (1H), 8.20 (1H),8.37 (1H), 10.76 (1H), 12.09 (1H)

Example 243N-4-[(6RS)-6-[(tert-Butylsulfonyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide

A mixture comprisingN-4-[(6RS)-6-[(tert-butylsulfanyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide(191; 39 mg, 84 μmol), mCPBA (36 mg, 75%) and DMA (2.5 mL) was stirredat RT. After 16 h a second portion mCPBA (9 mg, 75%) was added. Themixture was stirred at RT for 4 h, DMSO (750 μL) was added, the mixtureconcentrated and purified by preparative HPLC (basic method) to give thetitle compound (25 mg, 57%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35 (9H), 2.08 (3H), 2.44 (1H), 2.56(1H), 2.78-2.91 (2H), 3.24-3.39 (3H), 6.57 (2H), 6.61 (1H), 7.03 (2H),7.18 (1H), 7.35 (1H), 8.09 (1H), 8.24 (1H), 10.32 (1H), 12.02 (1H)

Example 244(6RS)-2-2-[(2-Fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,N,6-trimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide244-2: Methyl(6RS)-3-anilino-2-{2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate

A solution of 2-fluoro-2-methylpropanoic acid (340 μL, 3.59 mmol) andHATU (1.36 g, 3.59 mmol) in DMA (13 mL) was added to a mixture of methyl(6RS)-2-(2-aminopyridin-4-yl)-3-anilino-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate(141-2; 700 mg, 1.79 mmol) and DIPEA (625 μL, 3.59 mmol) in DMA (13 mL)and the reaction was stirred at RT for 16 h. The mixture wasconcentrated, EtOAc was added, the mixture washed with water, brine anddried over sodium sulfate. After filtration and removal of the solvent,the mixture was purified Biotage (SNAP NH 28 g, EtOAc:Hexane) to givethe title compound (603 mg, 67%).

244-1:(6RS)-3-Anilino-2-{2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid

A mixture of methyl(6RS)-3-anilino-2-{2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate(244-2; 1.600 mg, 1.25 mmol), lithium hydroxide (7.5 mL, 1M in water),THF (22 mL) and MeOH (7 mL) was stirred at RT for 16 h. Citric acid (506mg) in water (10 mL) was added and the mixture concentrated. Theprecipitate was washed with water and dried to give the title compound(304 mg, 50%).

(6RS)-2-2-[(2-Fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,N,6-trimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A solution of(6RS)-3-anilino-2-{2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (244-1; 43 mg, 92 μmol) and HATU (70 mg, 185 μmol) in DMA (1 mL)was added to a mixture of N-methylmethanamine (139 μL, 2M in THF) andDIPEA (48 μL, 277 μmol) in DMA (1 mL) and the reaction was stirred at RTfor 1 h. The mixture was concentrated and purified by preparative TLC(MeOH:DCM) to give the title compound (19 mg, 40%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39 (3H), 1.54 (3H), 1.59 (3H), 2.44(1H), 2.77 (1H), 2.90 (1H), 2.93 (6H), 3.49 (1H), 6.52 (2H), 6.59 (1H),6.99 (2H), 7.20 (1H), 7.40 (1H), 8.11 (1H), 8.12 (1H), 9.70 (1H), 11.90(1H)

Example 245(6RS)-2-2-[(2-Fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,6-dimethyl-4-oxo-3-phenylamino)-N-propyl-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A solution of(6RS)-3-anilino-2-{2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (244-1; 43 mg, 92 μmol) and HATU (70 mg, 185 μmol) in DMA (1 mL)was added to a mixture of N-methylpropan-1-amine (28 μL, 277 μmol) andDIPEA (48 μL, 277 μmol) in DMA (1 mL) and the reaction was stirred at RTfor 1 h. The mixture was concentrated and purified by preparative TLC(MeOH:DCM) to give the title compound (19 mg, 37%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.70 (3H), 1.39 (2H), 1.43 (3H), 1.57(3H), 1.61 (3H), 2.45 (1H), 2.78 (1H), 2.94 (2H), 3.01 (3H), 3.13 (1H),3.52 (1H), 6.55 (2H), 6.61 (1H), 7.01 (2H), 7.22 (1H), 7.38 (1H),8.11-8.16 (2H), 9.68 (1H), 11.89 (1H)

Example 246(6RS)—N,N-Diethyl-2-2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A solution of(6RS)-3-anilino-2-{2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (244-1; 43 mg, 92 μmol) and HATU (70 mg, 185 μmol) in DMA (1 mL)was added to a mixture of N-ethylethanaminium chloride (30 mg, 277 μmol)and DIPEA (97 μL, 554 μmol) in DMA (1 mL) and the reaction was stirredat RT for 1 h. The mixture was concentrated and purified by preparativeTLC (MeOH:DCM) to give the title compound (21 mg, 41%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03 (6H), 1.41 (3H), 1.57 (3H), 1.61(3H), 2.47 (1H), 2.75 (1H), 2.93 (1H), 3.18-3.43 (4H), 3.44 (1H), 6.55(2H), 6.61 (1H), 7.01 (2H), 7.23 (1H), 7.38 (1H), 8.11-8.16 (2H), 9.67(1H), 11.91 (1H)

Example 247(6RS)-2-2-[(2-Fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,6-dimethyl-N-(2-methylpropyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A solution of(6RS)-3-anilino-2-{2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (244-1; 43 mg, 92 μmol) and HATU (70 mg, 185 μmol) in DMA (1 mL)was added to a mixture of N,2-dimethylpropan-1-amine (33 μL, 277 μmol)and DIPEA (48 μL, 277 μmol) in DMA (1 mL) and the reaction was stirredat RT for 1 h. The mixture was concentrated and purified by preparativeTLC (MeOH:DCM) to give the title compound (18 mg, 35%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.57 (3H), 0.68 (3H), 1.43 (3H), 1.57(3H), 1.61 (3H), 1.74 (1H), 2.41 (1H), 2.79 (1H), 2.84 (1H), 2.95 (1H),3.11 (3H), 3.26 (1H), 3.57 (1H), 6.55 (2H), 6.62 (1H), 7.01 (2H), 7.20(1H), 7.35 (1H), 8.10-8.15 (2H), 9.67 (1H), 11.88 (1H)

Example 248(6RS)-2-2-[(2-Fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,6-dimethyl-4-oxo-3-(phenylamino)-N-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A solution of(6RS)-3-anilino-2-{2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (244-1; 43 mg, 92 μmol) and HATU (70 mg, 185 μmol) in DMA (1 mL)was added to a mixture of 3,3,3-trifluoro-N-methylpropan-1-aminiumchloride (45 mg, 277 μmol) and DIPEA (97 μL, 554 μmol) in DMA (1 mL) andthe reaction was stirred at RT for 1 h. The mixture was concentrated andpurified by preparative TLC (MeOH:DCM) to give the title compound (24mg, 43%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.41 (3H), 1.57 (3H), 1.61 (3H), 2.35(2H), 2.47 (1H), 2.77 (1H), 2.96 (1H), 3.15 (3H), 3.36 (1H), 3.52 (2H),6.55 (2H), 6.61 (1H), 7.01 (2H), 7.23 (1H), 7.37 (1H), 8.11-8.17 (2H),9.68 (1H), 11.91 (1H)

Example 249(6RS)—N-(Cyclopropylmethyl)-2-2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide

A solution of(6RS)-3-anilino-2-{2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (244-1; 43 mg, 92 μmol) and HATU (70 mg, 185 μmol) in DMA (1 mL)was added to a mixture of cyclopropyl-N-methylmethanaminium chloride (34mg, 277 μmol) and DIPEA (97 μL, 554 μmol) in DMA (1 mL) and the reactionwas stirred at RT for 1 h. The mixture was concentrated and purified bypreparative TLC (MeOH:DCM) to give the title compound (10 mg, 19%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.06 (1H), 0.14 (1H), 0.31 (1H), 0.37(1H), 0.83 (1H), 1.43 (3H), 1.57 (3H), 1.61 (3H), 2.45 (1H), 2.80 (1H),2.95 (1H), 3.07 (1H), 3.09 (3H), 3.27 (1H), 3.54 (1H), 6.55 (2H), 6.61(1H), 7.01 (2H), 7.22 (1H), 7.39 (1H), 8.10-8.15 (2H), 9.68 (1H), 11.90(1H)

Example 2502-Fluoro-2-methyl-N-4-[(6RS)-6-methyl-4-oxo-3-(phenylamino)-6-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylpropanamide

A solution of(6RS)-3-anilino-2-{2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylicacid (244-1; 43 mg, 92 μmol) and HATU (70 mg, 185 μmol) in DMA (1 mL)was added to a mixture of pyrrolidine (23 μL, 277 μmol) and DIPEA (48μL, 277 μmol) in DMA (1 mL) and the reaction was stirred at RT for 1 h.The mixture was concentrated and purified by preparative TLC (MeOH:DCM)to give the title compound (20 mg, 41%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.36 (3H), 1.58 (3H), 1.61 (3H), 1.79(4H), 2.49 (1H), 2.83 (1H), 2.88 (1H), 3.14-3.79 (5H), 6.55 (2H), 6.61(1H), 7.02 (2H), 7.24 (1H), 7.42 (1H), 8.10-8.17 (2H), 9.68 (1H), 11.92(1H)

Example 251N-{4-[(6RS)-3-Anilino-6-{[(4-fluorophenyl)sulfanyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide

A mixture of[(6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (151-1; 75 mg, 160 μmol) and sodium4-fluorobenzenethiolate (156 mg, 960 μmol) in DMA (3 mL) was stirred at100° C. for 5 h. Water was added, the mixture concentrated and purifiedby preparative HPLC (basic method) and preparative TLC (MeOH:DCM) togive the title compound (40 mg, 47%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.07 (3H), 2.30-2.39 (2H), 2.46 (1H),2.71 (1H), 3.06-3.18 (3H), 6.54 (2H), 6.59 (1H), 7.00 (2H), 7.14 (1H),7.18 (2H), 7.33 (1H), 7.46 (2H), 8.08 (1H), 8.22 (1H), 10.35 (1H), 11.95(1H)

Example 252N-(4-{(6RS)-3-Anilino-6-[(isopropylsulfonyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)morpholine-4-carboxamide

A mixture of(6RS)-2-(2-aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one(194; 30 mg, 68 μmol) and morpholine-4-carbonyl chloride (24 μL, 205μmol) in pyridine (0.8 mL) was stirred at RT for 2 days. The mixture wasconcentrated and purified by preparative TLC (MeOH:DCM) to give thetitle compound (12 mg, 31%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.26 (6H), 2.41 (1H), 2.76-2.89 (2H),3.14 (1H), 3.23-3.33 (3H), 3.45 (4H), 3.54-3.62 (5H), 6.57 (2H), 6.61(1H), 7.02 (2H), 7.11 (1H), 7.35 (1H), 7.91 (1H), 8.02 (1H), 9.11 (1H),11.99 (1H)

Example 253N-{4-[(6RS)-3-Anilino-6-{[(3,4-dichlorophenyl)sulfanyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide

A mixture of[(6RS)-2-(2-Acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (151-1; 75 mg, 160 μmol), sodium3,4-dichlorobenzenethiolate (193 mg, 960 μmol) in DMA (3 mL) was stirredat 100° C. for 5 h. The mixture was concentrated and purified bypreparative TLC (MeOH:DCM) to give the title compound (59 mg, 66%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.07 (3H), 2.37 (1H), 2.41-2.49 (2H),2.72 (1H), 3.13 (1H), 3.18 (1H), 3.26 (1H), 6.55 (2H), 6.60 (1H), 7.01(2H), 7.15 (1H), 7.34 (1H), 7.38 (1H), 7.56 (1H), 7.65 (1H), 8.08 (1H),8.22 (1H), 10.35 (1H), 11.95 (1H)

Example 254N-{4-[(6RS)-3-Anilino-6-{[(4-chlorophenyl)sulfanyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamicle

A mixture of[(6RS)-2-(2-Acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (151-1; 75 mg, 160 μmol), sodium4-chlorobenzenethiolate (160 mg, 960 μmol) in DMA (3 mL) was stirred at100° C. for 5 h. The mixture was concentrated and purified bypreparative TLC (MeOH:DCM) to give the title compound (50 mg, 60%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.07 (3H), 2.32-2.48 (3H), 2.72 (1H),3.09-3.17 (2H), 3.20 (1H), 6.54 (2H), 6.59 (1H), 7.01 (2H), 7.15 (1H),7.32-7.43 (5H), 8.08 (1H), 8.22 (1H), 10.34 (1H), 11.95 (1H)

Example 255N-4-[(6RS)-6-[(4-Fluoro-3-methoxyphenyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide

A mixture of[(6RS)-2-(2-Acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (151-1; 75 mg, 160 μmol), sodium4-fluoro-3-methoxybenzenethiolate (173 mg, 960 μmol) in DMA (3 mL) wasstirred at 100° C. for 5 h. The mixture was concentrated and purified bypreparative TLC (MeOH:DCM) to give the title compound (34 mg, 38%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.07 (3H), 2.29-2.48 (3H), 2.70 (1H),3.05 (1H), 3.09-3.16 (2H), 3.81 (3H), 6.54 (2H), 6.59 (1H), 7.00 (2H),7.10-7.16 (2H), 7.20 (1H), 7.33 (1H), 7.35 (1H), 8.08 (1H), 8.22 (1H),10.35 (1H), 11.94 (1H)

Example 256N-4-[(6RS)-6-[(3,4-Difluorophenyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide

A mixture of[(6RS)-2-(2-Acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (151-1; 75 mg, 160 μmol), sodium3,4-difluorobenzenethiolate (161 mg, 960 μmol) in DMA (3 mL) was stirredat 1001 for 5 h. The mixture was concentrated and purified bypreparative TLC (MeOH:DCM) to give the title compound (41 mg, 46%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.07 (3H), 2.31-2.47 (3H), 2.71 (1H),3.10-3.17 (2H), 3.21 (1H), 6.55 (2H), 6.60 (1H), 7.01 (2H), 7.15 (1H),7.23 (1H), 7.34 (1H), 7.40 (1H), 7.55 (1H), 8.08 (1H), 8.22 (1H), 10.35(1H), 11.94 (1H)

Example 257N-4-[(6RS)-6-[(4-Methoxyphenyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide

A mixture of[(6RS)-2-(2-Acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (151-1; 75 mg, 160 μmol), sodium4-methoxybenzenethiolate (156 mg, 960 μmol) in DMA (3 mL) was stirred at100° C. for 5 h. The mixture was concentrated and purified bypreparative TLC (MeOH:DCM) to give the title compound (54 mg, 60%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.07 (3H), 2.26-2.37 (2H), 2.38-2.47(1H), 2.70 (1H), 2.98 (1H), 3.06 (1H), 3.13 (1H), 3.73 (3H), 6.54 (2H),6.59 (1H), 6.92 (2H), 7.00 (2H), 7.14 (1H), 7.33 (1H), 7.38 (2H), 8.08(1H), 8.22 (1H), 10.35 (1H), 11.94 (1H)

Example 258 Methyl(6RS)-4-oxo-2-(pyridin-4-yl)-3-(pyridin-2-ylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate258-2: Methyl(1RS)-3-hydroxy-5-oxo-4-(pyridin-2-ylcarbamothioyl)cyclohex-3-ene-1-carboxylate

To a solution of methyl(1RS)-3-hydroxy-5-oxocyclohex-3-ene-1-carboxylate (4.96 g, 29.2 mmol;commercially available from FCH Group Company) and2-isothiocyanatopyridine (3.97 g, 29.2 mmol) in MeCN (100 mL) was addedTEA (1.64 mL, 11.7 mmol) and the mixture was stirred at reflux for 16 h.Ethyl acetate was added, the mixture washed with water and brine anddried over sodium sulfate. After filtration and concentration theresidue was purified by Biotage (SNAP silica 100 g, EtOAc:Hexane) togive the title compound (1.35 g, 14%).

258-1: Methyl(1RS)-5-oxo-4-(pyridin-2-ylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-ene-1-carboxylate

A solution of methyl(1RS)-3-hydroxy-5-oxo-4-(pyridin-2-ylcarbamothioyl)cyclohex-3-ene-1-carboxylate(258-2; 1.35 g, 4.41 mmol) and 1-(pyridin-4-yl)methanamine (895 μL, 8.81mmol) in DMA (5 mL) was heated at 120° C. for 1.5 h. The mixtu re wasconcentrated and purified by Biotage (SNAP silica 100 g, MeOH:DCM) togive the title compound (280 mg, 14%).

Methyl(6RS)-4-oxo-2-(pyridin-4-yl)-3-(pyridin-2-ylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate

A mixture of methyl(1RS)-3-hydroxy-5-oxo-4-(pyridin-2-ylcarbamothioyl)cyclohex-3-ene-1-carboxylate(258-1; 275 mg, 693 μmol), hydrogen peroxide (34% in water, 121 μL, 1.39mmol) in MeOH (25 mL) was heated at 90° C. for 24 h. The mixtu re wasconcentrated and purified by Biotage (SNAP silica 50 g, MeOH:DCM) togive the title compound (35 mg, 14%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.57 (2H), 3.12 (1H), 3.18 (1H), 3.37(1H), 3.64 (3H), 6.37 (1H), 6.58 (1H), 7.38 (1H), 7.52 (2H), 7.94 (1H),8.02 (1H), 8.45 (2H), 12.01 (1H)

Example 259(6RS)-2-(2-Aminopyridin-4-yl)-3-anilino-6-[(isopropylsulfanyl)methyl]-6-methyl-1,5,6,7-tetrahydro-4H-indol-4-one259-1:[(6RS)-3-Anilino-6-methyl-2-{2-[(methylsulfonyl)amino]pyridin-4-yl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate

A solution of(6RS)-2-(2-aminopyridin-4-yl)-6-(hydroxymethyl)-6-methyl-3-(phenylamino)-1,5,6,7-tetrahydro-4H-indol-4-one(228; 6.70 g, 18.5 mmol), DMAP (452 mg, 3.70 mmol) and methanesulfonylchloride (2.15 mL, 27.7 mmol) in pyridine (100 mL) was stirred at RT for4 h. MeOH was added, the mixture concentrated and purified by Biotage(SNAP silica 340 g, MeOH:DCM) and by crystallization from MeOH to givethe title compound (873 mg, 9%).

(6RS)-2-(2-Aminopyridin-4-yl)-3-anilino-6-[(isopropylsulfanyl)methyl]-6-methyl-1,5,6,7-tetrahydro-4H-indol-4-one

A mixture of[(6RS)-3-anilino-6-methyl-2-{2-[(methylsulfonyl)amino]pyridin-4-yl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (259-1; 100 mg, 227 μmol), sodium propane-2-thiolate(134 mg, 1.36 mmol) in DMA (3.2 mL) was stirred at 100° C. for 5 h. Themixture was concentrated and purified by preparative TLC (MeOH:DCM) togive the title compound (8 mg, 8%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07 (3H), 1.17 (6H), 2.24 (1H), 2.39(1H), 2.66 (2H), 2.74 (1H), 2.83 (1H), 2.95 (1H), 5.73 (2H), 6.52-6.61(4H), 6.70 (1H), 7.01 (2H), 7.23 (1H), 7.76 (1H), 11.70 (1H)

Example 260N-(4-{(6RS)-3-Anilino-4-oxo-6-[(1,3-thiazol-2-ylsulfonyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)acetamide

A mixture comprisingN-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(1,3-thiazol-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)acetamide(231; 45 mg, 92 μmol), mCPBA (48 mg, 75%) and DMA (2.5 mL) was stirredat RT for 16 h, DMSO was added, the mixture filtered and purified bypreparative HPLC (basic method) to give the title compound (6 mg, 14%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.23 (3H), 2.44 (2H), 2.77 (1H), 2.87(1H), 3.25 (1H), 3.81 (1H), 3.89 (1H), 6.57 (2H), 6.61 (1H), 7.03 (2H),7.20 (1H), 7.36 (1H), 8.19-8.25 (2H), 8.35 (1H), 8.48 (1H), 10.41 (1H),12.08 (1H)

Example 261N-{4-[(6RS)-3-Anilino-6-{[(4-fluoro-3-hydroxyphenyl)sulfanyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide

A mixture of[(6RS)-2-(2-Acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonate (151-1; 75 mg, 160 μmol), sodium4-fluoro-3-methoxybenzenethiolate (173 mg, 960 μmol) in DMA (3 mL) wasstirred at 1001 for 5 h. The mixture was concentrated and purified bypreparative TLC (MeOH:DCM) to give the title compound (34 mg, 38%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.07 (3H), 2.27-2.37 (2H), 2.44 (1H),2.69 (1H), 3.00 (1H), 3.07 (1H), 3.12 (1H), 6.54 (2H), 6.59 (1H), 6.91(1H), 7.00 (2H), 7.07 (1H), 7.15 (1H), 7.26 (1H), 7.33 (1H), 8.08 (1H),8.22 (1H), 10.04 (1H), 10.34 (1H), 11.94 (1H)

Example 262N-{4-[(6RS)-3-Anilino-6-{[(2-methoxyethyl)sulfonyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide

A mixture comprisingN-4-[(6RS)-6-[(2-methoxyethyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide(229; 46 mg, 99 μmol), mCPBA (52 mg, 75%) and DMA (2.5 mL) was stirredat RT for 16 h, DMSO was added, the mixture filtered and purified bypreparative HPLC (basic method) to give the title compound (7 mg, 13%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.07 (3H), 2.39 (1H), 2.47 (1H),2.79-2.90 (1H), 3.20-3.35 (4H), 3.28 (3H), 3.44 (2H), 3.71 (2H), 6.56(2H), 6.60 (1H), 7.02 (2H), 7.17 (1H), 7.36 (1H), 8.08 (1H), 8.24 (1H),10.35 (1H), 12.02 (1H)

Example 263N-{4-[(6RS)-3-Anilino-6-{[(4-fluorobenzyl)sulfonyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide

A mixture comprisingN-4-[(6RS)-6-[(4-fluorobenzyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide(233; 55 mg, 107 μmol), mCPBA (56 mg, 75%) and DMA (2.5 mL) was stirredat RT 16 h, DMSO was added, the mixture filtered and purified bypreparative HPLC (basic method) to give the title compound (8 mg, 14%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.07 (3H), 2.38 (1H), 2.47 (1H),2.79-2.91 (2H), 3.21-3.31 (3H), 4.57 (2H), 6.56 (2H), 6.60 (1H), 7.02(2H), 7.17 (1H), 7.26 (2H), 7.36 (1H), 7.46 (2H), 8.09 (1H), 8.24 (1H),10.35 (1H), 12.03 (1H)

The compounds of examples 264 to 311 have been prepared according to thegeneral procedures outlined in schemes 1 to 19 and in analogy to theexperiments described for examples 1 to 263:

Structure IUPAC-Name Mass found (M + 1) Example ¹H-NMR 264

(6RS)-4-oxo-2-(pyridin-4-yl)-3-(pyridin-2-ylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylic acid MS (ES+): m/z = 349 ¹H-NMR (400 MHz, DMSO-d6),δ [ppm] = 2.53-2.56 (2H), 3.10 (2H), 3.38-3.52 (1H), 6.36 (1H), 6.58(1H), 7.37 (1H), 7.51 (2H), 7.94 (1H), 8.00 (1H), 8.44 (2H), 11.96 (1H)265

tert-butyl(6RS)-4-oxo-3-(phenylamino)-2-pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxylate MS (ES+): m/z = 404 ¹H-NMR (400 MHz, DMSO-d6), δ[ppm] = 1.37 (9H), 2.52-2.61 (2H), 3.08-3.18 (2H), 3.22 (1H), 6.57 (2H),6.62 (1H), 7.03 (2H), 7.43-7.48 (3H), 8.42 (2H), 12.00 (1H) 266

(6RS)-N,N-dimethyl-4-oxo-2-(pyridin-4-yl)-3-(pyridin-2-ylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide MS (ES+): m/z = 376 ¹H-NMR (400 MHz,DMSO-d6), δ [ppm] = 2.31 (1H), 2.47 (1H), 2.85 (3H), 2.92- 3.04 (2H),3.07 (3H), 3.64 (1H), 6.38 (1H), 6.59 (1H), 7.38 (1H), 7.52 (2H), 7.96(1H), 7.99 (1H), 8.45 (2H), 11.97 (1H) 267

(6RS)-N-[(2S)-2-hydroxypropyl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide MS (ES+): m/z = 419¹H-NMR (400 MHz, DMSO-d6), δ [ppm] = 1.00 + 1.06 (3H), 2.24-2.40 (1H),2.44- 2.59 (1H), 2.87 + 3.11 (3H), 2.91-3.21 (3H), 3.27-3.47 (1H),3.60-3.87 (2H), 4.68 + 4.90 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H),7.42-7.48 (3H), 8.41 (2H), 11.93 + 11.95 (1H) 268

(6RS)-N-[(2R)-2-hydroxypropyl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide MS (ES+): m/z = 419¹H-NMR (400 MHz, DMSO-d6), δ [ppm] = 1.00 + 1.06 (3H), 2.25-2.39 (1H),2.45- 2.59 (1H), 2.87 + 3.11 (3H), 2.92-3.20 (3H), 3.27-3.47 (1H),3.60-3.86 (2H), 4.68 + 4.90 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H),7.43-7.48 (3H), 8.41 (2H), 11.95 (1H) 269

(6RS)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-N-[2-(pyrrolidin-1-yl)ethyl]-4,5,6,7-tetrahydro-1H-indole-6-carboxamide MS (ES+): m/z = 458¹H-NMR (400 MHz, DMSO-d6), δ [ppm] = 1.61-1.71 (4H), 2.29-2.36 (1H),2.41- 2.55 (6H), 2.58 (1H), 2.86 + 3.07 (3H), 2.89-3.06 (2H), 3.38-3.58(2H), 3.64 (1H), 6.59 (2H), 6.63 (1H), 7.04 (2H), 7.43-7.47 (3H), 8.41(2H), 11.95 (1H) 270

(6RS)-N-methyl-N-[2-(morpholin-4-yl)ethyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide MS (ES+): m/z= 474 ¹H-NMR (400 MHz, DMSO-d6), δ [ppm] = 2.29-2.59 (8H), 2.87 + 3.07(3H), 2.91- 3.05 (2H), 3.40-3.58 (6H), 3.65 (1H), 6.59 (2H), 6.64 (1H),7.05 (2H), 7.43-7.48 (3H), 8.41 (2H), 11.95 (1H) 271

(6RS)-N-cyclobutyl-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide MS (ES+): m/z = 415 1H-NMR (400 MHz,DMSO-d6), δ [ppm] = 1.55-1.67 (2H), 1.95-2.36 (5H), 2.41- 2.57 (1H),2.84 + 3.00 (3H), 2.91-3.06 (2H), 3.60 + 3.72 (1H), 4.62 + 4.84 (1H),6.60 (2H), 6.64 (1H), 7.05 (2H), 7.43 (1H), 7.46 (2H), 8.41 (2H), 11.95(1H) 274

(6RS)-N-[(2S)-1-methoxypropan-2-yl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide MS (ES+): m/z= 433 ¹H-NMR (400 MHz, DMSO-d6), δ [ppm] = 1.00 + 1.10 (3H), 2.22-2.39(1H), 2.54- 2.60 (1H), 2.69 + 2.90 (3H), 2.91-3.08 (2H), 3.22 + 3.25 +3.30 (3H), 3.24-3.31 (1H), 3.39 (1H), 3.64 (1H), 4.28 + 4.73 (1H), 6.60(2H), 6.64 (1H), 7.05 (2H), 7.42-7.48 (3H), 8.41 (2H), 11.94 (1H) 275

(6RS)-N-(1-methoxy-2-methylpropan-2-yl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide MS (ES+):m/z = 447 ¹H-NMR (400 MHz, DMSO-d6), δ [ppm] = 1.31 (6H), 2.29 + 2.33(1H), 2.39-2.47 (1H), 2.91-3.03 (2H), 2.97 (3H), 3.20 (3H), 3.49 (1H),3.58 (1H), 3.66 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.43 (1H), 7.44(2H), 8.40 (2H), 11.91 (1H) 276

(−) methyl (6R or6S)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylate MS (ES+): m/z = 380.1 ¹H-NMR (400MHz, DMSO-d6), δ [ppm] = 2.54-2.66 (2H), 3.11 (1H), 3.18 (1H), 3.36(1H), 3.64 (3H), 6.54 (2H), 6.59 (1H), 6.98 (2H), 7.39 (1H), 7.54 (1H),8.25 (1H), 8.50 (1H), 11.73 (1H) 277

(+) methyl (6S or6R)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylate MS (ES+): m/z = 380.1 ¹H-NMR(400 MHz,DMSO-d6), δ [ppm] = 2.54-2.66 (2H), 3.11 (1H), 3.18 (1H), 3.36 (1H),3.64 (3H), 6.54 (2H), 6.59 (1H), 6.98 (2H), 7.39 (1H), 7.54 (1H), 8.25(1H), 8.50 (1H), 11.73 (1H) 278

(+)-(6S or 6R)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylic acid MS (ES+): m/z = 366.1 ¹H-NMR (400MHz, DMSO-d6), δ [ppm] = 2.53-2.63 (2H), 3.06-3.19 (2H), 3.24 (1H), 6.55(2H), 6.59 (1H), 6.98 (2H), 7.39 (1H), 7.54 (1H), 8.24 (1H), 8.50 (1H),11.70 (1H), 12.59 (1H) 279

(−)-(6R or 6S)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylic acid MS (ES+): m/z = 366.1 ¹H-NMR (400MHz, DMSO-d6), δ [ppm] = 2.53-2.63 (2H), 3.06-3.19 (2H), 3.24 (1H), 6.55(2H), 6.59 (1H), 6.98 (2H), 7.39 (1H), 7.54 (1H), 8.24 (1H), 8.50 (1H),11.70 (1H), 12.59 (1H) 280

(+)-(6S or6R)-2-(3-fluoropyridin-4-yl)-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide MS (ES+): m/z = 393.2 ¹H-NMR(400 MHz, DMSO-d6), δ [ppm] = 2.34 (1H), 2.50 (1H), 2.85 (3H), 2.94-3.03 (2H), 3.06 (3H), 3.66 (1H), 6.57 (2H), 6.59 (1H), 6.99 (2H), 7.39(1H), 7.53 (1H), 8.24 (1H), 8.49 (1H), 11.66 (1H) 281

(−)-(6R or6S)-2-(3-fluoropyridin-4-yl)-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide MS (ES+): m/z = 393.2 ¹H-NMR(400 MHz, DMSO-d6), δ [ppm] = 2.34 (1H), 2.50 (1H), 2.85 (3H), 2.94-3.03 (2H), 3.06 (3H), 3.66 (1H), 6.57 (2H), 6.59 (1H), 6.99 (2H), 7.39(1H), 7.53 (1H), 8.24 (1H), 8.49 (1H), 11.66 (1H) 282

(6RS)-6-(2-hydroxypropan-2-yl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one MS (ES+): m/z = 362 ¹H-NMR (400 MHz, DMSO-d6),δ [ppm] = 1.14 (3H), 1.16 (3H), 2.15 (1H), 2.25- 2.39 (2H), 2.71 (1H),2.97 (1H), 4.44 (1H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.42 (1H), 7.47(2H), 8.41 (2H), 11.90 (1H) 283

(6R or6S)-6-(2-hydroxypropan-2-yl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7tetrahydro-4H-indol-4-one MS (ES+): m/z = 362 ¹H-NMR (400 MHz, DMSO-d6),δ [ppm] = 1.14 (3H), 1.16 (3H), 2.15 (1H), 2.25- 2.39 (2H), 2.71 (1H),2.97 (1H), 4.44 (1H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.42 (1H), 7.47(2H), 8.41 (2H), 11.90 (1H) 284

(6S or6R)-6-(2-hydroxypropan-2-yl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7tetrahydro-4H-indol-4-one MS (ES+): m/z = 362 ¹H-NMR (400 MHz, DMSO-d6),δ [ppm] = 1.14 (3H), 1.16 (3H), 2.15 (1H), 2.25- 2.39 (2H), 2.71 (1H),2.97 (1H), 4.44 (1H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.42 (1H), 7.47(2H), 8.41 (2H), 11.90 (1H) 285

N-{4-[(6RS)-6-(2-hydroxypropan-2-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide MS (ES+): m/z = 419.21H-NMR (400 MHz, DMSO-d6), δ [ppm] = 1.14 (3H), 1.15 (3H), 2.07 (3H),2.13 (1H), 2.24-2.38 (2H), 2.67 (1H), 2.99 (1H), 4.42 (1H), 6.56 (2H),6.60 (1H), 7.01 (2H), 7.16 (1H), 7.34 (1H), 8.08 (1H), 8.23 (1H), 10.34(1H), 11.91 (1H) 286

N-{4-[(6RS)-6-(2-hydroxypropan-2-yl)-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide MS (ES+): m/z =433 ¹H-NMR (400 MHz, DICHLOROMETHANE-d2), δ [ppm] = 1.12 (3H), 1.32(6H), 2.22 (3H), 2.29 (1H), 2.68 (1H), 2.84 (1H), 3.32 (1H), 6.72 (2H),6.79 (1H), 7.00 (1H), 7.08-7.18 (3H), 7.97 (1H), 8.21 (1H), 8.37 (1H),9.73 (1H) 287

(6RS)-2-(3-fluoropyridin-4-yl)-6-(2-hydroxypropan-2-yl)-3-(phenylamino)-1,5,6,7-tetrahydro-4H-indol-4-one MS (ES+): m/z = 380.2 ¹H-NMR (400 MHz,DMSO-d6), δ [ppm] = 1.14 (3H), 1.15 (3H), 2.14 (1H), 2.25- 2.40 (2H),2.66 (1H), 2.99 (1H), 4.43 (1H), 6.54 (2H), 6.59 (1H), 6.98 (2H), 7.39(1H), 7.50 (1H), 8.24 (1H), 8.49 (1H), 11.61 (1H) 288

(6RS)-3-(phenylamino)-6-(prop-2-en-1-yl)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one MS (ES+): m/z = 344.3 ¹H-NMR (400 MHz, DMSO-d6), δ [ppm]= 2.17-2.37 (5H), 2.59 (1H), 2.95 (1 H), 5.07 (1H), 5.10 (1H), 5.84(1H), 6.57 (2H), 6.62 (1H), 7.03 (2H), 7.42-7.47 (3H), 8.40 (2H), 11.89(1H) 290

(6RS)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-3-(phenylamino)-6-(prop-2-en-1-yl)-1,5,6,7-tetrahydro-4H-indol-4-one MS (ES+): m/z = 418 ¹H-NMR(400MHz, DMSO-d6), δ [ppm] = 2.15-2.37 (5H), 2.58 (1H), 2.93 (1H), 3.38(3H), 3.75 (2H), 4.28 (2H), 5.07 (1H), 5.10 (1H), 5.84 (1H), 6.53 (2H),6.58 (1H), 6.98 (2H), 7.30 (1H), 7.39 (1H), 8.03 (1H), 8.38 (1H), 11.15(1H) 291

(6RS)-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-3-(phenylamino)-6-(prop-2-en-1-yl)-1,5,6,7-tetrahydro-4H-indol-4-one MS (ES+): m/z = 414 ¹H-NMR (400MHz, DMSO-d6), δ [ppm] = 0.33 (2H), 0.55 (2H), 1.128 (1H), 2.17- 2.36(5H), 2.56 (1H), 2.95 (1H), 3.93 (2H), 5.07 (1H), 5.10 (1H), 5.84 (1H),6.51 (2H), 6.56 (1H), 6.96 (2H), 7.26 (1H), 7.35 (1H), 8.02 (1H), 8.31(1H), 11.24 (1H) 294

(6RS)-3-[(3-fluorophenyl)amino]-6-(hydroxymethyl)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-indol-4-one MS (ES+):m/z = 426.2 ¹H-NMR (400 MHz, DMSO-d6), δ [ppm] = 2.23 (1H), 2.28-2.36(2H), 2.66 (1H), 2.94 (1H), 3.37 (3H), 3.44 (2H), 3.72 (2H), 4.29 (2H),4.74 (1H), 6.20 (1H), 6.32 (1H), 6.37 (1H), 6.99 (1H), 7.33 (1H), 7.58(1H), 8.09 (1H), 8.41 (1H), 11.27 (1H) 296

(6RS)-6-({[2-(dimethylamino)ethyl](methyl)amino}methyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one MS (ES+): m/z = 418.3¹H-NMR (400 MHz, DMSO-d6), δ [ppm] = 2.12-2.46 (18H), 2.60 (1H), 3.01(1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.42-7.48 (3H), 8.40 (2H), 11.89(1H) 297

(6RS)-6-{[4-(dimethylamino)piperidin-1-yl]methyl}-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one MS (ES+): m/z = 444.3¹H-NMR (400 MHz, DMSO-d6), δ [ppm] = 1.36 (2H), 1.71 (2H), 1.83 (1H),1.93 (1H), 2.01 (1H), 2.14-2.28 (2H), 2.16 (6H), 2.28-2.38 (2H),2.40-2.49 (1H), 2.58 (1H), 2.83 (1H), 2.90 (1H), 3.03 (1H), 6.58 (2H),6.63 (1H), 7.04 (2H), 7.42-7.48 (3H), 8.40 (2H), 11.90 (1H) 298

(6RS)-6-[(4-methylpiperazin-1-yl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one MS (ES+): m/z = 416.3 ¹H-NMR (400 MHz,DMSO-d6), δ [ppm] = 2.16 (3H), 2.18 (1H), 2.25-2.62 (13H), 3.03 (1H),6.58 (2H), 6.63 (1H), 7.04 (2H), 7.43-7.47 (3H), 8.40 (2H), 11.91 (1H)299

4-fluoro-N-{4-[(6RS)-4-oxo-3-(phenylamino)-6-{[(RS)-propan-2-ylsulfinyl]methyl}-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}benzamideMS (ES+): m/z = 545 ¹H-NMR (400 MHz, DMSO-d6), δ [ppm] = 1.19 (6H), 2.42(1H), 2.53-2.55 (1H), 2.68-2.91 (5H), 3.20 (1H), 6.58-6.63 (3H), 7.03(2H), 7.25 (1H), 7.35 (2H), 7.43 (1H), 8.10 (2H), 8.18 (1H), 8.34 (1H),10.74 (1H), 12.07 (1H) 300

N-{4-[(6RS)-4-oxo-3-(phenylamino)-6-{[(RS)-propan-2-ylsulfinyl]methyl}-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}-1,3-thiazole-5-carboxamideMS (ES+): m/z = 534 ¹H-NMR (400 MHz, DMSO-d6), δ [ppm] = 1.12-1.25 (6H),2.42 (1H), 2.53-2.55 (1H), 2.67-2.91 (5H), 3.20 (1H), 6.57-6.64 (3H),7.03 (2H), 7.27 (1H), 7.43 (1H), 8.20 (1H), 8.30 (1H), 8.88 (1H), 9.33(1H), 11.11 (1H), 12.07 (1H) 301

(1S,2S)-2-fluoro-N-{4-[(6RS)-4-oxo-3-(phenylamino)-6-{[(RS)-propan-2-ylsulfinyl]methyl}-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}cyclopropanecarboxamide MS (ES+): m/z = 509 ¹H-NMR (400 MHz,DMSO-d6), δ [ppm] = 1.12-1.24 (7H), 1.58-1.69 (1H), 2.20 (1H), 2.41(1H), 2.46-2.55 (1H), 2.66-2.90 (5H), 3.19 (1H), 4.93 (1H), 6.57 (2H),6.60 (1H), 7.02 (2H), 7.17 (1H), 7.38 (1H), 8.09 (1H), 8.26 (1H), 10.73(1H), 12.03 (1H) 302

4-chloro-N-{4-[(6RS)-4-oxo-3-(phenylamino)-6-{[(RS)-propan-2-ylsulfinyl]methyl}-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}benzamideMS (ES+): m/z = 561 ¹H-NMR (400 MHz, DMSO-d6), δ [ppm] = 1.19 (6H), 2.42(1H), 2.53-2.56 (1H), 2.68-2.91 (5H), 3.20 (1H), 6.58-6.63 (3H), 7.03(2H), 7.26 (1H), 7.43 (1H), 7.59 (2H), 8.03 (2H), 8.19 (1H), 8.34 (1H),10.80 (1H), 12.07 (1H) 303

3,4-dichloro-N-{4-[(6RS)-4-oxo-3-(phenylamino)-6-{[(RS)-propan-2-ylsulfinyl]methyl}-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}benzamideMS (ES+): m/z = 595 ¹H-NMR (400 MHz, DMSO-d6), δ [ppm] = 1.19 (6H), 2.42(1H), 2.53-2.56 (1H), 2.67-2.91 (5H), 3.21 (1H), 6.57-6.64 (3H), 7.03(2H), 7.27 (1H), 7.44 (1H), 7.81 (1H), 7.97 (1H), 8.20 (1H), 8.27 (1H),8.33 (1H), 10.93 (1H), 12.07 (1H) 304

(6RS)-6-(aminomethyl)-3-[(3-fluorophenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-indol-4-one MS (ES+):m/z = 425.2 ¹H-NMR (400 MHz, DMSO-d6), δ [ppm] = 1.68 (2H), 2.11-2.30(2H), 2.36 (1H), 2.56-2.70 (3H), 2.94 (1H), 3.37 (3H), 3.72 (2H), 4.29(2H), 6.20 (1H), 6.32 (1H), 6.37 (1H), 6.99 (1H), 7.33 (1H), 7.58 (1H),8.09 (1H), 8.41 (1H), 11.25 (1H) 305

(6RS)-N-({3-[(3-fluorophenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl}methyl)acetamide MS (ES+): m/z =467.5 ¹H-NMR (400 MHz, DMSO-d6), δ [ppm] = 1.84 (3H), 2.21-2.35 (2H),2.43-2.55 (1H), 2.60 (1H), 2.90 (1H), 3.07-3.23 (2H), 3.37 (3H), 3.72(2H), 4.29 (2H), 6.20 (1H), 6.32 (1H), 6.37 (1H), 6.99 (1H), 7.33 (1H),7.57 (1H), 7.99 (1H), 8.10 (1H), 8.41 (1H), 11.29 (1H) 306

(+)-methyl (6S or6R)-2-(2-aminopyridin-4-yl)-3-[(3-fluorophenyl)amino]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxylate MS (ES+): m/z =409.2 1H-NMR (400 MHz, DMSO-d6), δ [ppm] = 1.32 (3H), 2.46 (1H), 2.64(1H), 2.90 (1H), 3.30 (1H), 3.55 (3H), 5.80 (2H), 6.16 (1H), 6.29-6.37(2H), 6.58 (1H), 6.69 (1H), 7.01 (1H), 7.57 (1H), 7.80 (1H), 11.81 (1H)307

(−)-methyl (6R or6S)-2-(2-aminopyridin-4-yl)-3-[(3-fluorophenyl)amino]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxylate MS (ES+): m/z =409.2 1H-NMR (400 MHz, DMSO-d6), δ [ppm] = 1.32 (3H), 2.46 (1H), 2.64(1H), 2.90 (1H), 3.30 (1H), 3.55 (3H), 5.80 (2H), 6.16 (1H), 6.29-6.37(2H), 6.58 (1H), 6.69 (1H), 7.01 (1H), 7.57 (1H), 7.80 (1H), 11.81 (1H)308

(6RS)-2-(2-aminopyridin-4-yl)-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylic acid MS (ES+): m/z = 377 ¹H-NMR (400MHz, DMSO-d6), δ [ppm] = 1.31 (3H), 2.39 (1H), 2.62 (1H), 2.84 (1H),3.28 (1H), 6.53 (2H), 6.55-6.61 (2H), 6.68 (1H), 7.01 (2H), 7.25 (1H),7.76 (1H), 11.73 (1H) 309

(6S or6R)-2-(2-aminopyridin-4-yl)-3-[(3-fluorophenyl)amino]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxylic acid hydrochloride MS (ES+):m/z = 395.1 ¹H-NMR (400 MHz, DMSO-d6), δ [ppm] = 1.32 (3H), 2.43 (1H),2.63 (1H), 2.90 (1H), 3.34 (1H), 6.32 (1H), 6.36-6.44 (2H), 6.95 (1H),7.05 (1H), 7.12 (1H), 7.71 (2H), 7.85 (1H), 7.94 (1H), 12.60 (2H), 13.57(1H) 310

(6R or6S)-2-(2-aminopyridin-4-yl)-3-[(3-fluorophenyl)amino]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxylic acid hydrochloride MS (ES+):m/z = 395.1 ¹H-NMR (400 MHz, DMSO-d6), δ [ppm] = 1.32 (3H), 2.43 (1H),2.63 (1H), 2.90 (1H), 3.34 (1H), 6.32 (1H), 6.36-6.44 (2H), 6.95 (1H),7.05 (1H), 7.12 (1H), 7.71 (2H), 7.85 (1H), 7.94 (1H), 12.60 (2H), 13.57(1H) 311

(6RS)-3-[(3-fluorophenyl)amino]-6-(hydroxymethyl)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-6-methyl-1,5,6,7-tetrahydro-4H-indol-4-oneMS (ES+): m/z = 440.2 ¹H-NMR (400 MHz, DMSO-d6), δ [ppm] = 0.98 (3H),2.07 (1H), 2.39 (1H), 2.57 (1H), 2.95 (1H), 3.20-3.32 (2H), 3.37 (3H),3.73 (2H), 4.29 (2H), 4.87 (1H), 6.19 (1H), 6.32 (1H), 6.37 (1H), 7.00(1H), 7.35 (1H), 7.58 (1H), 8.09 (1H), 8.41 (1H), 11.23 (1H)

Biological Investigations

The following assays can be used to illustrate the commercial utility ofthe compounds according to the present invention.

Examples were tested in selected biological assays one or more times.When tested more than once, data are reported as either average valuesor as median values, wherein

-   -   the average value, also referred to as the arithmetic mean        value, represents the sum of the values obtained divided by the        number of times tested and    -   the median value represents the middle number of the group of        values when ranked in ascending or descending order. If the        number of values in the data set is odd, the median is the        middle value. If the number of values in the data set is even,        the median is the arithmetic mean of the two middle values.

Examples were synthesized one or more times. When synthesized more thanonce, data from biological assays represent average values calculatedutilizing data sets obtained from testing of one or more syntheticbatch.

Biological Assay 1.0:

Bub1 kinase assay

Bub1-inhibitory activities of compounds described in the presentinvention were quantified using a time-resolved fluorescence energytransfer (TR-FRET) kinase assay which measures phosphorylation of thesynthetic peptide Biotin-Ahx-VLLPKKSFAEPG (SEQ ID No.1) (C-terminus inamide form), purchased from e.g. Biosyntan (Berlin, Germany) by the(recombinant) catalytic domain of human Bub1 (amino acids 704-1085),expressed in Hi5 insect cells with an N-terminal His6-tag and purifiedby affinity-(Ni-NTA) and size exclusion chromatography.

In a typical assay 11 different concentrations of each compound (0.1 nM,0.33 nM, 1.1 nM, 3.8 nM, 13 nM, 44 nM, 0.15 μM, 0.51 μM, 1.7 μM, 5.9 μMand 20 μM) were tested in duplicate within the same microtiter plate. Tothis end, 100-fold concentrated compound solutions (in DMSO) werepreviously prepared by serial dilution (1:3.4) of 2 mM stocks in a clearlow volume 384-well source microtiter plate (Greiner Bio-One,Frickenhausen, Germany), from which 50 nl of compounds were transferredinto a black low volume test microtiter plate from the same supplier.Subsequently, 2 μL of Bub1 (the final concentration of Bub1 was adjusteddepending on the activity of the enzyme lot in order to be within thelinear dynamic range of the assay: typically ˜200 ng/mL were used) inaqueous assay buffer [50 mM Tris/HCl pH 7.5, 10 mM magnesium chloride(MgCl2), 200 mM potassium chloride (KCL), 1.0 mM dithiothreitol (DTT),0.1 mM sodium ortho-vanadate, 1% (v/v) glycerol, 0.01% (w/v) bovineserum albumine (BSA), 0.005% (v/v) Trition X-100 (Sigma), 1× CompleteEDTA-free protease inhibitor mixture (Roche)] were added to thecompounds in the test plate and the mixture was incubated for 15 min at22° C. to allow pre-equilibration of the putative enzyme-inhibitorcomplexes before the start of the kinase reaction, which was initiatedby the addition of 3 μL 1.67-fold concentrated solution (in assaybuffer) of adenosine-tri-phosphate (ATP, 10 μM final concentration) andpeptide substrate (1 μM final concentration). The resulting mixture (5μL final volume) was incubated at 22° C. during 60 min. and the reactionwas stopped by the addition of 5 μL of an aqueous EDTA-solution (50 mMEDTA, in 100 mM HEPES pH 7.5 and 0.2% (w/v) bovine serum albumin) whichalso contained the TR-FRET detection reagents (0.2 μM streptavidin-XL665[Cisbio Bioassays, Codolet, France] and 1 nM anti-phosho-Serine antibody[Merck Millipore, cat. #35-002] and 0.4 nM LANCE EU-W1024 labeledanti-mouse IgG antibody [Perkin-Elmer, product no. AD0077, alternativelya Terbium-cryptate-labeled anti-mouse IgG antibody from Cisbio Bioassayscan be used]). The stopped reaction mixture was further incubated 1 h at22° C. in order to allow the formation of complexes between peptides anddetection reagents. Subsequently, the amount of product was evaluated bymeasurement of the resonance energy transfer from theEu-chelate-antibody complex recognizing the Phosphoserine residue to thestreptavidin-XL 665 bound to the biotin moiety of the peptide. To thisend, the fluorescence emissions at 620 nm and 665 nm after excitation at330-350 nm were measured in a TR-FRET plate reader, e.g. a Rubystar orPherastar (both from BMG Labtechnologies, Offenburg, Germany) or aViewlux (Perkin-Elmer) and the ratio of the emissions (665 nm/622 nm)was taken as indicator for the amount of phosphorylated substrate. Thedata were normalised using two sets of control wells for high—(=enzymereaction without inhibitor=0%=Minimum inhibition) and low—(=all assaycomponents without enzyme=100%=Maximum inhibition) Bub1 activity. IC₅₀values were calculated by fitting the normalized inhibition data to a4-parameter logistic equation (Minimum, Maximum, IC₅₀, Hill;Y=Max+(Min−Max)/(1+(X/IC₅₀)Hill)).

TABLE 1 Inhibition of Bub1 kinase Example IC₅₀ Nr. [nM] 1 13 2 62 3 1254 33 5 29 6 37 7 70 8 10 9 117 10 10 11 32 12 10 13 20 14 10 15 14 16 4517 9 18 8 19 16 20 21 21 25 22 30 23 14 24 10 25 7 26 13 27 47 28 24 2927 30 8 31 40 32 9 33 16 34 291 35 19 36 8 37 85 39 14 40 5 41 52 42 3843 65 44 37 45 6010 46 12 47 13 48 7 49 179 50 9 51 8 52 64 53 103 54 1555 23 56 55 57 69 58 4 59 4 60 14 61 17 62 5 63 4 64 21 65 44 66 19 67116 68 88 69 34 70 34 71 37 72 46 73 19 74 7 75 22 76 7 77 20 78 8 79 3780 10 81 6 82 68 83 16 84 29 85 3 86 28 87 83 88 153 89 66 90 232 91 1692 37 93 94 94 15 95 83 96 57 97 13 98 27 99 22 100 65 101 53 102 5 10315 104 19 105 14 106 16 107 12 108 35 109 11 110 27 111 21 112 32 113 25114 14 115 21 116 62 117 56 118 49 119 29 120 31 121 19 122 7 123 19 12438 125 46 126 47 127 47 128 38 129 30 130 14 131 81 132 91 133 29 134 18135 19 136 11 137 173 138 12 139 18 140 65 141 91 142 6 143 7 144 169145 40 146 59 147 61 148 27 149 17 150 10 151 7 152 13 153 12 154 11 15514 156 9 157 7 158 106 159 18 160 5 161 56 162 8 163 13 164 11 165 161166 573 167 10 168 17 169 26 170 13 171 22 172 400 173 15 174 1690 175103 176 131 177 153 178 60 179 932 180 588 181 52 182 2360 183 89 1841820 185 925 186 1150 187 156 188 480 189 8 190 8 191 19 192 49 193 411194 63 195 5 196 8 197 7 198 15 199 13 200 38 202 25 203 7 204 29 205 38206 22 207 19 208 11 209 16 210 81 211 11 212 37 213 206 214 88 215 19216 11 217 11 218 17 219 15 220 32 221 40 222 119 223 19 224 142 225 37226 18 227 73 228 32 229 8 230 10 231 8 232 12 233 70 234 18 235 13 23630 237 119 238 247 239 8 240 13 241 56 242 11 243 27 244 60 245 194 246127 247 639 248 1610 249 1090 250 241 251 42 252 19 253 236 254 56 25528 256 31 257 31 258 28 259 136 260 97 261 19 262 9 263 25 264 462 26529 266 40 267 15 268 18 269 27 270 20 271 10 274 27 275 58 276 10 277 19278 30 279 55 280 5 281 23 282 5 283 4 284 9 285 7 286 10 287 7 288 3290 10 291 10 294 296 11 297 60 298 52 299 60 300 92 301 94 302 99 303261 304 nd 305 nd 306 nd 307 nd 308 639 309 nd 310 nd 311 nd nd: notdetermined

The invention claimed is:
 1. A compound of formula (I),

wherein: R¹ is hydrogen or C₁-C₆-alkyl; R² is hydroxy, C₂-C₄-alkenyl,R⁷R⁸N—, R¹⁰—O—C(O)—, R⁷R⁸N—C(O)—, R⁶—C(O)—NR⁹—, or R¹¹—(C₁-C₄-alkyl)-,wherein said C₂-C₄-alkenyl is optionally substituted with halogen,R¹⁰—O—C(O)—, R⁷R⁸N- or phenyl, wherein said phenyl group is optionallysubstituted, one or more times with R⁴; R³ is hydrogen or C₁-C₆-alkyl; Ais a group selected from:

wherein * indicates the point of attachment of said group with the restof the molecule and said group is optionally substituted, one or moretimes with R⁴; each R⁴ is independently halogen, hydroxy, nitro, cyano,C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy,C₁-C₄-hydroxyalkyl, C₁-C₄-alkyl-C(O)—, R¹⁰—O—C(O)—, R⁷R⁸N—C(O)—,C₁-C₄-alkyl-C(O)—NH—, R⁷R⁸N—, or R⁷R⁸N—SO₂—; E is a group

wherein * indicates the point of attachment of said group with the restof the molecule; each R⁵ is independently halogen, hydroxy, nitro,cyano, R⁹R¹⁰N—, (R¹³—C(O)—)(R¹⁴—C(O)—)N—, C₁-C₄-alkyl, C₃-C₆-cycloalkyl,C₁-C₆-alkoxy, C₁-C₄-haloalkyl, C₁-C₆-haloalkoxy, R⁶—C(O)—NR⁹— orR⁷R⁸N—C(O)—NR⁹—, wherein said C₁-C₄-alkoxy is optionally substituted,one or more times, independently from each other, with a substituentselected from hydroxy, C₁-C₄-alkoxy, C₃-C₆-cycloalkyl, and 4- to6-membered heterocycloalkyl; Q is O or N—OH; each R⁶ is independentlyC₁-C₆-alkyl, C₃-C₆-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenylor heteroaryl, wherein said C₁-C₆-alkyl is optionally substituted, oneor more times, independently from each other, with halogen, hydroxy,nitro, cyano, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₃-C₆-cycloalkyl, R⁷R⁸N-or phenyl optionally substituted, one or more times with R⁴, whereinsaid C₃-C₆-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl orheteroaryl groups are optionally substituted, one or more times,independently from each other, with halogen, hydroxy, nitro, cyano,C₁-C₆-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyl, R¹⁰—O—C(O)— orC₁-C₄-haloalkoxy; R⁷ and R⁸ are independently hydrogen, C₁-C₆-alkyl,C₃-C₆-cycloalkyl, R¹⁰—O—C(O)— or phenyl, wherein said C₁-C₆-alkyl isoptionally substituted, one or more times, independently from eachother, with halogen, hydroxy, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,C₃-C₆-cycloalkyl optionally substituted one time with hydroxy, 4- to6-membered heterocycloalkyl, heteroaryl, or R⁹R¹⁰N—, wherein said phenylgroup is optionally substituted, one or more times with R⁴; or, R⁷ andR⁸ together with the nitrogen atom to which they are attached form a 4-to 7-membered nitrogen containing heterocyclic ring, optionallycontaining one additional heteroatom selected from O, NR⁹ and S, andwhich may be optionally substituted, one or more times with R¹²; whereintwo R¹² substituents attached to the same ring carbon atom areoptionally taken together with the carbon atom to which they areattached to form a cyclobutane, azetidine, or oxetane group; saidazetidine being optionally substituted one time with C₁-C₃-alkyl; or, R⁷and R⁸ together with the nitrogen atom to which they are attached form agroup selected from:

wherein * indicates the point of attachment of said group with the restof the molecule; R⁹ is hydrogen or C₁-C₆-alkyl; R¹⁰ is hydrogen,C₁-C₆-alkyl or C₃-C₆-cycloalkyl; R¹¹ is hydroxy, nitro, cyano,C₃-C₆-cycloalkyl, 4- to 6-membered heterocycloalkyl, C₁-C₄-alkyl-C(O)—,R¹⁰—O—C(O)—, R⁷R⁸N—C(O)—, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, R⁷R⁸N—, N₃—,R⁶—C(O)—NR⁹—, R⁶—O—C(O)—NR⁹—, R⁷R⁸N—C(O)—NR⁹—, R⁶—SO₂—NR⁹—, R⁶—S—,R⁶—SO—, R⁶—SO₂—, or R⁷R⁸N—SO₂—, wherein said C₃-C₆-cycloalkyl or 4- to6-membered heterocycloalkyl groups are optionally substituted, one ormore times, independently from each other, with halogen, hydroxy, cyano,C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyl or C₁-C₄-haloalkoxy, whereinsaid C₁-C₄-alkoxy is optionally substituted with phenyl, wherein saidphenyl group is optionally substituted, one or more times with R⁴; eachR¹² is independently halogen, hydroxy, C₁-C₄-alkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy, or R⁹R¹⁰N—; R¹³ and R¹⁴ areindependently C₁-C₄-alkyl, or C₃-C₆-cycloalkyl, wherein saidC₃-C₆-cycloalkyl is optionally substituted, one or more times,independently from each other, with halogen; and m is 0, 1 or 2; or anN-oxide, a salt, a tautomer or a stereoisomer of said compound, or asalt of said N-oxide, tautomer or stereoisomer.
 2. The compound offormula (I) according to claim 1: wherein: R¹ is hydrogen orC₁-C₄-alkyl; R² is hydroxy, C₂-C₄-alkenyl, R⁷R⁸N—, R⁷R⁸N—C(O)—,R⁶—C(O)—NR⁹—, or R¹¹—(C₁-C₄-alkyl)-; wherein said C₂-C₄-alkenyl isoptionally substituted with halogen, R¹⁰—O—C(O)—, R⁷R⁸N— or phenyl,wherein said phenyl group is optionally substituted, one or more timeswith R⁴; R³ is hydrogen or C₁-C₄-alkyl; A is a group selected from:

wherein * indicates the point of attachment of said group with the restof the molecule and said group is optionally substituted, one or moretimes with R⁴; each R⁴ is independently halogen, hydroxy, nitro, cyano,C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyl, or C₁-C₄-haloalkoxy; E is agroup

wherein * indicates the point of attachment of said group with the restof the molecule; each R⁵ is independently halogen, hydroxy, cyano,R⁹R¹⁰N—, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy,R⁶—C(O)—NR⁹— or R⁷R⁸N—C(O)—NR⁹—, wherein said C₁-C₄-alkoxy is optionallysubstituted, one or more times, independently from each other, with asubstituent selected from hydroxy, C₁-C₄-alkoxy, and C₃-C₆-cycloalkyl; Qis O or N—OH; each R⁶ is independently C₁-C₆-alkyl, C₃-C₆-cycloalkyl, 4-to 6-membered heterocycloalkyl, phenyl or heteroaryl, wherein saidC₁-C₆-alkyl is optionally substituted, one or more times, independentlyfrom each other, with halogen, hydroxy, cyano, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy, C₃-C₆-cycloalkyl, R⁷R⁸N- or phenyl optionallysubstituted, one or more times with R⁴, wherein said C₃-C₆-cycloalkyl,4- to 6-membered heterocycloalkyl, phenyl or heteroaryl groups areoptionally substituted, one or more times, independently from eachother, with halogen, hydroxy, cyano, C₁-C₄-alkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkyl, R¹⁰—O—C(O)— or C₁-C₄-haloalkoxy; R⁷ and R⁸ areindependently hydrogen, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, R¹⁰—O—C(O)— orphenyl, wherein said C₁-C₆-alkyl is optionally substituted, one or moretimes, independently from each other, with halogen, hydroxy,C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₃-C₆-cycloalkyl optionally substitutedone time with hydroxy, 4- to 6-membered heterocycloalkyl, heteroaryl, orR⁹R¹⁰N—, wherein said phenyl group is optionally substituted, one ormore times with R⁴; or R⁷ and R⁸ together with the nitrogen atom towhich they are attached form a 4- to 7-membered nitrogen containingheterocyclic ring, optionally containing one additional heteroatomselected from O, NR⁹ and S, and which may be optionally substituted, oneor more times with R¹²; R⁹ is hydrogen or C₁-C₄-alkyl; R¹⁰ is hydrogen,C₁-C₄-alkyl, or C₃-C₄-cycloalkyl; R¹¹ is hydroxy, cyano,C₃-C₆-cycloalkyl, 4- to 6-membered heterocycloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy, R⁷R⁸N—, N₃—, R⁶—C(O)—NR⁹—, R⁶—O—C(O)—NR⁹—,R⁷R⁸N—C(O)—NR⁹—, R⁶—SO₂—NR⁹—, R⁶—S—, or R⁶—SO—, or R⁶—SO₂—, wherein saidC₃-C₆-cycloalkyl or 4- to 6-membered heterocycloalkyl groups areoptionally substituted, one or more times, independently from eachother, with halogen, hydroxy, cyano, C₁-C₄-alkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkyl or C₁-C₄-haloalkoxy, wherein said C₁-C₄-alkoxy isoptionally substituted with phenyl, wherein said phenyl group isoptionally substituted, one or more times with R⁴; each R¹² isindependently halogen, hydroxy, C₁-C₄-alkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy, or R⁹R¹⁰N—; and m is 0, 1 or 2, or anN-oxide, a salt, a tautomer or a stereoisomer of said compound, or asalt of said N-oxide, tautomer or stereoisomer.
 3. The compound offormula (I) according to claim 1, wherein: R¹ is hydrogen orC₁-C₂-alkyl; R² is hydroxy, C₂-C₄-alkenyl, R⁷R⁸N—, R¹⁰—O—C(O)—,R⁷R⁸N—C(O)—, R⁶—C(O)—NR⁹—, or R¹¹-(C₁-C₄-alkyl)-, wherein saidC₂-C₄-alkenyl is optionally substituted with R¹⁰—O—C(O)—, R⁷R⁸N- orphenyl, wherein said phenyl group is optionally substituted, one or moretimes with R⁴; R³ is hydrogen or C₁-C₄-alkyl; A is a group selectedfrom:

wherein * indicates the point of attachment of said group with the restof the molecule and said group is optionally substituted, one or moretimes with R⁴; each R⁴ is independently halogen; E is a group

wherein * indicates the point of attachment of said group with the restof the molecule; each R⁵ is independently halogen, R⁹R¹⁰N—,C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, R⁶—C(O)—NR⁹— or R⁷R⁸N—C(O)—NR⁹—, whereinsaid C₁-C₄-alkoxy is optionally substituted, one or more times,independently from each other, with a substituent selected from hydroxy,C₁-C₄-alkoxy, and C₃-C₄-cycloalkyl; Q is O; each R⁶ is independentlyC₁-C₆-alkyl, C₃-C₆-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenylor heteroaryl, wherein said C₁-C₆-alkyl is optionally substituted, oneor more times, independently from each other, with halogen, hydroxy,C₁-C₂-alkoxy, C₃-C₄-cycloalkyl, R⁷R⁸N- or phenyl optionally substituted,one or more times with R⁴, wherein said C₃-C₆-cycloalkyl, 4- to6-membered heterocycloalkyl, phenyl or heteroaryl groups are optionallysubstituted, one or more times, independently from each other, withhalogen, hydroxy, C₁-C₄-alkyl, tert-butyl-O—C(O)—, or C₁-C₄-alkoxy; R⁷and R⁸ are independently hydrogen, C₁-C₆-alkyl, C₃-C₄-cycloalkyl,tert-butyl-O—C(O)— or phenyl, wherein said C₁-C₆-alkyl is optionallysubstituted, one or more times, independently from each other, withhalogen, hydroxy, C₁-C₄-alkoxy, C₃-C₆-cycloalkyl optionally substitutedone time with hydroxy, 4- to 6-membered heterocycloalkyl, heteroaryl, orR⁹R¹⁰N—, wherein said phenyl group is optionally substituted, one ormore times, independently from each other, with R⁴; or R⁷ and R⁸together with the nitrogen atom to which they are attached form a 4- to6-membered nitrogen containing heterocyclic ring, optionally containingone additional heteroatom selected from O and NR⁹, and which may beoptionally substituted, one or more times with R¹²; R⁹ is hydrogen orC₁-C₂-alkyl; R¹⁰ is hydrogen or C₁-C₄-alkyl; R¹¹ is hydroxy, 6-memberedheterocycloalkyl, C₁-C₂-alkoxy, R⁷R⁸N—, N₃—, R⁶—C(O)—NR⁹—,R⁶—O—C(O)—NR⁹—, R⁷R⁸N—C(O)—NR⁹—, R⁶—SO₂—NR⁹—, R⁶—SO—, or R⁶—SO₂—;wherein said 6-membered heterocycloalkyl group is optionallysubstituted, one or more times, independently from each other, withhalogen, hydroxy, cyano, C₁-C₄-alkoxy, C₁-C₄-haloalkyl orC₁-C₄-haloalkoxy, wherein said C₁-C₄-alkoxy is optionally substitutedwith phenyl, wherein said phenyl group is optionally substituted, one ormore times with R⁴; each R¹² is independently halogen, hydroxy,C₁-C₂-alkyl, or R⁹R¹⁰N—; and m is 0 or 1, or an N-oxide, a salt, atautomer or a stereoisomer of said compound, or a salt of said N-oxide,tautomer or stereoisomer.
 4. The compound of formula (I) according toclaim 1, wherein: R¹ is hydrogen or methyl; R² is hydroxy,C₂-C₄-alkenyl, R⁷R⁸N—, R¹⁰—O—C(O)—, R⁷R⁸N—C(O)—, R⁶—C(O)—NR⁹—, orR¹¹—(C₁-C₄-alkyl)-, wherein said C₂-C₄-alkenyl is optionally substitutedwith HO—C(O)—, (CH₃)₂N— or phenyl, wherein said phenyl group isoptionally substituted one, two or three times with F; R³ is hydrogen,methyl or ethyl; A is a group selected from:

wherein * indicates the point of attachment of said group with the restof the molecule and said group is optionally substituted, one or twotimes with R⁴; each R⁴ is independently fluoro or chloro; E is a group

wherein * indicates the point of attachment of said group with the restof the molecule; each R⁵ is independently fluoro, R⁹R¹⁰N—, C₁-C₂-alkoxy,difluoroethoxy, R⁶—C(O)—NR⁹— or R⁷R⁸N—C(O)—NR⁹—, wherein saidC₁-C₂-alkoxy is optionally substituted, one or two times, independentlyfrom each other, with a substituent selected from hydroxy, methoxy, andcyclopropyl; Q is O; each R⁶ is independently C₁-C₅-alkyl,C₃-C₄-cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl or 5- to6-membered heteroaryl, wherein said C₁-C₅-alkyl is optionallysubstituted, one, two or three times, independently from each other,with fluoro, hydroxy, methoxy, cyclopropyl, or R⁷R⁸N- and optionallysubstituted one time with phenyl optionally substituted, one, two orthree times, independently from each other, with R⁴, wherein saidC₃-C₄-cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl orheteroaryl groups are optionally substituted, one, two or three times,independently from each other, with fluoro, chloro, hydroxy, methyl,tert-butyl-O—C(O)—, or methoxy; R⁷ and R⁸ are independently hydrogen,C₁-C₅-alkyl, cyclopropyl, cyclobutyl, tert-butyl-O—C(O)— or phenyl,wherein said C₁-C₅-alkyl is optionally substituted, one or more times,independently from each other, with fluoro, hydroxy, methoxy,C₃-C₄-cycloalkyl optionally substituted one time with hydroxy,5-membered heterocycloalkyl, 5-membered heteroaryl, or R⁹R¹⁰N—, whereinsaid phenyl group is optionally substituted, one, or two times,independently from each other, with fluoro or chloro; or R⁷ and R⁸together with the nitrogen atom to which they are attached form a 4- to6-membered nitrogen containing heterocyclic ring, optionally containingone additional heteroatom selected from O and NR⁹, and which may beoptionally substituted, one or two times with R¹²; R⁹ is hydrogen ormethyl; R¹⁰ is hydrogen, methyl or tert-butyl; R¹¹ is hydroxy,morpholino, methoxy, R⁷R⁸N—, N₃—, R⁶—C(O)—NR⁹—, R⁶—O—C(O)—NR⁹—,R⁷R⁸N—C(O)—NR⁹—, R⁶—SO₂—NR⁹—, R⁶—S—, R⁶—SO—, or R⁶—SO₂—, wherein saidmethoxy group is optionally substituted with phenyl; each R¹² isindependently fluoro, hydroxy, methyl, or R⁹R¹⁰N—; and m is 0 or 1; oran N-oxide, a salt, a tautomer or a stereoisomer of said compound, or asalt of said N-oxide, tautomer or stereoisomer.
 5. The compoundaccording to claim 1, which is selected from the group consisting of:(6RS)-6-(hydroxymethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;tert-butyl[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamate;(6RS)-6-[(benzyloxy)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;tert-butyl[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]carbamate;(6RS)-6-amino-3-anilino-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-onehydrochloride;N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]cyclopropanecarboxamide;(6RS)-4-oxo-N-phenyl-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;methyl(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxylate;4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxylicacid;(6RS)—N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-4-oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-(2-hydroxyethyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;methyl(6RS)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylate;methyl(6RS)-2-(3-methoxypyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylate;(6RS)—N-(2-methoxyethyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-ethyl-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-6-(morpholin-4-ylcarbonyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-3-(phenylamino)-2-(pyridin-4-yl)-6-(pyrrolidin-1-ylcarbonyl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-6-(azetidin-1-ylcarbonyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)—N-(cyclopropylmethyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-(cyclopropylmethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-methyl-4-oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N,N-dimethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-ethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-tert-butyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-3-(phenylamino)-6-(piperidin-1-ylcarbonyl)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-4-oxo-3-(phenylamino)-N-(propan-2-yl)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-6-(hydroxymethyl)-6-methyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;methyl(6RS)-2-(2-aminopyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylate;(6RS)-6-(azidomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-6-[(dimethylamino)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-6-(hydroxymethyl)-1-methyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-6-[tert-butyl(dimethyl)silyl]oxy-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-1-ethyl-6-(hydroxymethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-1-[2-(dimethylamino)ethyl]-6-(hydroxymethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-6-hydroxy-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-6-ethenyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;1-ethyl-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylurea;1-cyclopropyl-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylurea;1-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-3-propan-2-ylurea;1-(furan-2-ylmethyl)-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylurea;1-(3-chloro-4-fluorophenyl)-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylurea;methyl[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamate;N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylacetamide;N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonamide;(6RS)-2-(3-methoxypyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylicacid; methyl(6RS)-2-[2-(acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylate;(4E)-5-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]pent-4-enoicacid;(4Z)-5-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]pent-4-enoicacid;(6RS)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylicacid;(6RS)-6-[(E)-2-(4-fluorophenyl)ethenyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-6-[(Z)-2-(4-fluorophenyl)ethenyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-6-(morpholin-4-ylmethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-6-[methyl(propan-2-yl)amino]methyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-6-[(1E)-3-(dimethylamino)prop-1-en-1-yl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-6-[(1Z)-3-(dimethylamino)prop-1-en-1-yl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;1-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-3-(2RS)-(tetrahydrofuran-2-ylmethyl)urea;(6RS)—N-methyl-4-oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6R)—N-methyl-4-oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N,N-dimethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6R)—N,N-dimethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6S)—N,N-dimethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6S)—N-methyl-4-oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-6-[(ethylsulfanyl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;4-fluoro-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylbenzenesulfonamide;2-methoxyethyl[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamate;2-fluoroethyl[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamate;(6RS)-6-[(1,3-benzothiazol-2-ylsulfanyl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-2-[2-(acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylicacid;N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcyclopropanecarboxamide;2-methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylpropanamide;2-methoxy-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylacetamide;N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcyclobutanecarboxamide;N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylpropane-2-sulfonamide;(6RS)—N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6R)—N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6S)—N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-2-(3-fluoropyridin-4-yl)-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-2-(3-methoxypyridin-4-yl)-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-2-(3-fluoropyridin-4-yl)-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-(2-hydroxyethyl)-2-(3-methoxypyridin-4-yl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-6-[(ethylsulfonyl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;3-methoxy-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylpropanamide;(6RS)-2-[2-(acetylamino)pyridin-4-yl]-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-2-[2-(acetylamino)pyridin-4-yl]-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;methyl(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxylate;methyl(6R)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxylate;methyl(6S)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxylate;(6RS)-2-(2-aminopyridin-4-yl)-6-(hydroxymethyl)-3-(phenylamino)-1,5,6,7-tetrahydro-4H-indol-4-one;4-fluoro-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylbenzamide;tert-butyl[(2S)-1-oxo-1-([(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylamino)propan-2-yl]carbamate;tert-butyl(2S)-2-([(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamoyl)pyrrolidine-1-carboxylate;(2S)-2-hydroxy-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylpropanamide;N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-1,3-thiazole-2-carboxamide;1-methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-1H-pyrrole-2-carboxamide;N-4-[(6RS)-6-(hydroxymethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide;N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyltetrahydro-2H-pyran-4-carboxamide;N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylfuran-2-carboxamide;(6RS)—N-(2-hydroxy-2-methylpropyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-[(2S)-2-hydroxypropyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-(1-hydroxy-2-methylpropan-2-yl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-(2,2-dimethylpropyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-(2-methylpropyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-methyl-N-(2-methylpropyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-[2-(dimethylamino)ethyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-[2-(dimethylamino)ethyl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-methyl-N-[2-(methylamino)ethyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-(2,2-difluoroethyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-N-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-N-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-(2,2-difluoroethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-tert-butyl-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-[(1-hydroxycyclopropyl)methyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-(2-hydroxy-2-methylpropyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-N-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-N-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-[(2R)-2-hydroxypropyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxylicacid;(6R)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxylicacid;(6S)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxylicacid;(6RS)-6-[(4-methylpiperazin-1-yl)carbonyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-6-[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-6-[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-6-[(3-hydroxyazetidin-1-yl)carbonyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)—N,N-diethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]acetamide;2-methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]propanamide;3-methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide;3-hydroxy-3-methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide;2-cyclopropyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]acetamide;(3S)-3-hydroxy-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide;3-hydroxy-2,2-dimethyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]propanamide;(6RS)—N-[(2S)-1-hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6R)—N-[(2S)-1-hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6S)—N-[(2S)-1-hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-[(2R)-1-hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6R)—N-[(2R)-1-hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(3R)-3-hydroxy-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide;(6S)—N-[(2R)-1-hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-[2-(methylamino)ethyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-L-prolinamide;tert-butylmethyl(3-oxo-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]aminopropyl)carbamate;methyl(6RS)-2-[2-([rel-(1R,2R)-2-fluorocyclopropyl]carbonylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylate;(6RS)-6-[(1,3-benzothiazol-2-ylsulfonyl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-2-[2-([(1R,2R)-2-fluorocyclopropyl]carbonylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylicacid;(6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylicacid; methyl(6RS)-2-2-[(4-fluorobenzoyl)amino]pyridin-4-yl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylate;methyl(6RS)-4-oxo-3-(phenylamino)-2-2-[(1,3-thiazol-5-ylcarbonyl)amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indole-6-carboxylate;3,3-dimethyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide;(6RS)-2-2-[(4-fluorobenzoyl)amino]pyridin-4-yl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylicacid;(6RS)-4-oxo-3-(phenylamino)-2-2-[(1,3-thiazol-5-ylcarbonyl)amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indole-6-carboxylicacid;N³-methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]-beta-alaninamidetrifluoroacetate;(6RS)—N-[(1-hydroxycyclobutyl)methyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(4E)-5-[(6RS)-2-[2-(acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-yl]pent-4-enoicacid; methyl(6RS)-2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylate;N-4-[(6RS)-6-(azidomethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide;(6RS)—N-(2-methoxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-2-[2-([rel-(1R,2R)-2-fluorocyclopropyl]carbonylamino)pyridin-4-yl]-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-2-[2-([rel-(1R,2R)-2-fluorocyclopropyl]carbonylamino)pyridin-4-yl]-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-(2,2-dimethylpropyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;N-4-[(6RS)-6-(aminomethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide;Methyl(6RS)-3-anilino-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxylate;(6RS)-3-Anilino-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxylicacid;(6RS)-2-[3-(Cyclopropylmethoxy)pyridin-4-yl]-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;Methyl(6RS)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylate;(6RS)-3-Anilino-2-[3-(2-methoxyethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxylicacid;(6RS)-2-[3-(2-Methoxyethoxy)pyridin-4-yl]-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-(2-Hydroxyethyl)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;Methyl(6RS)-3-anilino-2-[3-(2-hydroxyethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxylate;(6RS)-2-[3-(2-Hydroxyethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylicacid;(6RS)-2-[3-(2,2-Difluoroethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylicacid;(6RS)—N-Ethyl-N-(2-hydroxyethyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-(2-Hydroxyethyl)-4-oxo-3-(phenylamino)-N-(propan-2-yl)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-[(1-Hydroxycyclobutyl)methyl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-[(2R)-1-Hydroxypropan-2-yl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-[(2S)-1-Hydroxypropan-2-yl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;N-(4-{(6RS)-3-Anilino-6-methyl-6-[(4-methylpiperazin-1-yl)carbonyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)acetamide;(6RS)-2-(2-Acetamidopyridin-4-yl)-3-anilino-N,N,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;N-{4-[(6RS)-3-Anilino-6-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]carbonyl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide;N-(4-{(6RS)-3-Anilino-6-[(3-fluoroazetidin-1-yl)carbonyl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)acetamide;N-(4-{(6RS)-3-Anilino-6-[(3,3-difluoroazetidin-1-yl)carbonyl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)acetamide;(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-(2-methoxyethyl)-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N,N-diethyl-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;N-4-[(6RS)-6-Methyl-6-(2-oxa-6-azaspiro[3.3]hept-6-ylcarbonyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide;(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-[(2S)-2-methoxypropyl]-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-[(2S)-1-methoxypropan-2-yl]-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-(2-methoxy-2-methylpropyl)-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N,6-dimethyl-4-oxo-3-(phenylamino)-N-propyl-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-(2,2-dimethylpropyl)-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;N-4-[(6RS)-6-[(3R)-3-(Dimethylamino)pyrrolidin-1-yl]carbonyl-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide;N-4-[(6RS)-6-Methyl-6-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide;(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N,6-dimethyl-N-(2-methylpropyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;N-4-[(6RS)-6-Methyl-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylcarbonyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamideN-4-[(6RS)-6-[(Ethylsulfanyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide;N-(4-(6RS)-4-Oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)acetamide;N-4-[(6RS)-6-[(tert-Butylsulfanyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide;(6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(S)-propan-2-ylsulfinyl]methyl-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-2-2-[(4-Fluorobenzoyl)amino]pyridin-4-yl-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-2-2-[(4-Fluorobenzoyl)amino]pyridin-4-yl-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N,N-Dimethyl-4-oxo-3-(phenylamino)-2-2-[(1,3-thiazol-5-ylcarbonyl)amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-(2-Hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-2-1(1,3-thiazol-5-ylcarbonyl)amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;N-{4-[(6RS)-3-Anilino-6-[(methylsulfonyl)amino]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl]acetamide;N-{4-[(6RS)-6-(Acetamidomethyl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide;N-[(6RS)-2-(2-Acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-4′-methoxybiphenyl-4-carboxamide;5-[(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-yl]pentanoicacid;(6RS)-3-Anilino-N,N-diisopropyl-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-3-Anilino-2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-N,N-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-3-Anilino-2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-N-(2-hydroxyethyl)-N-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-3-Anilino-2-[3-(2-hydroxyethoxy)pyridin-4-yl]-N,N-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-3-Anilino-2-[3-(2-hydroxyethoxy)pyridin-4-yl]-N-(2-hydroxyethyl)-N-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-3-Anilino-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-N,N-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;Methyl(6RS)-3-anilino-2-[2-({[(1RS)-2,2-difluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxylate;(6RS)-3-Anilino-2-[2-({[(1RS)-2,2-difluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxylicacid;(6RS)-3-Anilino-2-[2-({[(1RS)-2,2-difluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N,N-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;N-(4-{(6RS)-3-Anilino-6-[(isopropylsulfanyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)-4-fluoro-3-methoxybenzamide;N-(4-{(6RS)-3-Anilino-6-[(isopropylsulfanyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)-2-fluoro-2-methylpropanamide;1-(4-{(6RS)-3-Anilino-6-[(isopropylsulfanyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)-3-cyclopropylurea;1-(4-{(6RS)-3-Anilino-6-[(isopropylsulfonyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)-3-cyclopropylurea;N-{[(6RS)-3-Anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl}-L-alaninamide;(6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N,N,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-3-Anilino-N,N-diethyl-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N,6-dimethyl-4-oxo-N-propyl-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N-isobutyl-N,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-3-Anilino-N-(cyclopropylmethyl)-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N,6-dimethyl-4-oxo-N-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(1S,2S)—N-{4-[(6RS)-3-Anilino-6-methyl-4-oxo-6-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}-2-fluorocyclopropanecarboxamide;(1S,2S)—N-{4-[(6RS)-3-Anilino-6-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}-2-fluorocyclopropanecarboxamide;(1S,2S)—N-{4-[(6RS)-3-Anilino-6-methyl-4-oxo-6-(piperidin-1-ylcarbonyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}-2-fluorocyclopropanecarboxamide;N-{4-[(6RS)-3-Anilino-6-({[2-(dimethylamino)ethyl]sulfanyl}methyl)-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide;N-(4-{(6RS)-3-Anilino-6-[(isopropylsulfonyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)-4-fluoro-N-methylbenzamide;(6RS)-2-(2-Aminopyridin-4-yl)-6-(hydroxymethyl)-6-methyl-3-(phenylamino)-1,5,6,7-tetrahydro-4H-indol-4-one;N-4-[(6RS)-6-[(2-Methoxyethyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide;N-4-[(6RS)-6-[(1,3-Oxazol-2-ylsulfanyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide;N-(4-(6RS)-4-Oxo-3-(phenylamino)-6-[(1,3-thiazol-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)acetamide;N-(4-(6RS)-4-Oxo-3-(phenylamino)-6-[(pyridin-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)acetamide;N-4-[(6RS)-6-[(4-Fluorobenzyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide;(1S,2S)-2-Fluoro-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)cyclopropanecarboxamide;N-(4-(6RS)-4-Oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)-1,3-thiazole-5-carboxamide;4-Fluoro-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)benzamide;4-Chloro-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)benzamide;3,4-Dichloro-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)benzamide;N-4-[(6RS)-6-[(Ethylsulfonyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide;N-(4-(6RS)-4-Oxo-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)acetamide;2-Fluoro-2-methyl-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)propanamide;4-Fluoro-3-methoxy-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)benzamide;N-4-[(6RS)-6-[(tert-Butylsulfonyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide;(6RS)-2-2-[(2-Fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,N,6-trimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-2-2-[(2-Fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,6-dimethyl-4-oxo-3-(phenylamino)-N-propyl-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N,N-Diethyl-2-2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-2-2-[(2-Fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,6-dimethyl-N-(2-methylpropyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-2-2-[(2-Fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,6-dimethyl-4-oxo-3-(phenylamino)-N-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-(Cyclopropylmethyl)-2-2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;2-Fluoro-2-methyl-N-4-[(6RS)-6-methyl-4-oxo-3-(phenylamino)-6-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylpropanamide;N-{4-[(6RS)-3-Anilino-6-{[(4-fluorophenyl)sulfanyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide;N-(4-{(6RS)-3-Anilino-6-[(isopropylsulfonyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)morpholine-4-carboxamide;N-{4-[(6RS)-3-Anilino-6-{[(3,4-dichlorophenyl)sulfanyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide;N-{4-[(6RS)-3-Anilino-6-{[(4-chlorophenyl)sulfanyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide;N-4-[(6RS)-6-[(4-Fluoro-3-methoxyphenyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide;N-4-[(6RS)-6-[(3,4-Difluorophenyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide;N-4-[(6RS)-6-[(4-Methoxyphenyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide;Methyl(6RS)-4-oxo-2-(pyridin-4-yl)-3-(pyridin-2-ylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylate;(6RS)-2-(2-Aminopyridin-4-yl)-3-isopropylsulfanyl)methyl]-6-methyl-1,5,6,7-tetrahydro-4H-indol-4-one;N-(4-{(6RS)-3-Anilino-4-oxo-6-[(1,3-thiazol-2-ylsulfonyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)acetamide;N-{4-[(6RS)-3-Anilino-6-{[(4-fluoro-3-hydroxyphenyl)sulfanyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide;N-{4-[(6RS)-3-Anilino-6-{[(2-methoxyethyl)sulfonyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide;N-{4-[(6RS)-3-Anilino-6-{[(4-fluorobenzyl)sulfonyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide;(6RS)-4-oxo-2-(pyridin-4-yl)-3-(pyridin-2-ylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylicacid; tert-butyl(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxylate;(6RS)—N,N-dimethyl-4-oxo-2-(pyridin-4-yl)-3-(pyridin-2-ylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-[(2S)-2-hydroxypropyl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-[(2R)-2-hydroxypropyl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-N-[2-(pyrrolidin-1-yl)ethyl]-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-methyl-N-[2-(morpholin-4-yl)ethyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-cyclobutyl-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-[(2S)-1-methoxypropan-2-yl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)—N-(1-methoxy-2-methylpropan-2-yl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;methyl(6R)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylate;methyl(6S)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylate;(6S)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylicacid;(6R)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylicacid;(6S)-2-(3-fluoropyridin-4-yl)-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6R)-2-(3-fluoropyridin-4-yl)-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide;(6RS)-6-(2-hydroxypropan-2-yl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6R)-6-(2-hydroxypropan-2-yl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6S)-6-(2-hydroxypropan-2-yl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;N-{4-[(6RS)-6-(2-hydroxypropan-2-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide;N-{4-[(6RS)-6-(2-hydroxypropan-2-yl)-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide;(6RS)-2-(3-fluoropyridin-4-yl)-6-(2-hydroxypropan-2-yl)-3-(phenylamino)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-3-(phenylamino)-6-(prop-2-en-1-yl)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-3-(phenylamino)-6-(prop-2-en-1-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-3-(phenylamino)-6-(prop-2-en-1-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-3-[(3-fluorophenyl)amino]-6-(hydroxymethyl)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-6-({[2-(dimethylamino)ethyl](methyl)amino}methyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-6-{[4-(dimethylamino)piperidin-1-yl]methyl}-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)-6-[(4-methylpiperazin-1-yl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;4-fluoro-N-{4-[(6RS)-4-oxo-3-(phenylamino)-6-{[(RS)-propan-2-ylsulfinyl]methyl}-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}benzamide;N-{4-[(6RS)-4-oxo-3-(phenylamino)-6-{[(RS)-propan-2-ylsulfinyl]methyl}-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}-1,3-thiazole-5-carboxamide;(1S,2S)-2-fluoro-N-{4-[(6RS)-4-oxo-3-(phenylamino)-6-{[(RS)-propan-2-ylsulfinyl]methyl}-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}cyclopropanecarboxamide;4-chloro-N-{4-[(6RS)-4-oxo-3-(phenylamino)-6-{[(RS)-propan-2-ylsulfinyl]methyl}-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}benzamide;3,4-dichloro-N-{4-[(6RS)-4-oxo-3-(phenylamino)-6-{[(RS)-propan-2-ylsulfinyl]methyl}-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}benzamide;(6RS)-6-(aminomethyl)-3-[(3-fluorophenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-indol-4-one;(6RS)—N-({3-[(3-fluorophenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl}methyl)acetamide;methyl(6S)-2-(2-aminopyridin-4-yl)-3-[(3-fluorophenyl)amino]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxylate;methyl(6R)-2-(2-aminopyridin-4-yl)-3-[(3-fluorophenyl)amino]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxylate;(6RS)-2-(2-aminopyridin-4-yl)-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylicacid;(6S)-2-(2-aminopyridin-4-yl)-3-[(3-fluorophenyl)amino]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxylic;(6S)-2-(2-aminopyridin-4-yl)-3-[(3-fluorophenyl)amino]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxylicacid hydrochloride;(6R)-2-(2-aminopyridin-4-yl)-3-[(3-fluorophenyl)amino]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxylic;(6R)-2-(2-aminopyridin-4-yl)-3-[(3-fluorophenyl)amino]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-6-carboxylicacid hydrochloride; and(6RS)-3-[(3-fluorophenyl)amino]-6-(hydroxymethyl)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-6-methyl-1,5,6,7-tetrahydro-4H-indol-4-one,or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, ora salt of said N-oxide, tautomer or stereoisomer.
 6. A pharmaceuticalcomposition comprising at least one; compound according to claim 1,together with at least one pharmaceutically acceptable auxiliary.
 7. Acompound selected from:

wherein R¹, R², A, and E have the meaning according to claim 1; and

wherein R¹, R², E have the meaning according to claim 1.